Journal of Immunotoxicology, 2008; 5(4): 369–384 MHC restriction and allogeneic immune responses Dmitry B. Kazansky Carcinogenesis Institute, N. N. Blokhin's Cancer Research Center, Moscow, Russia Discovery of major histocompatability complex (MHC) restriction helped in the understanding of how T-lymphocytes recognize antigens on bacteria, viruses, and tumor cells. It was initially accepted that MHC restriction was a consequence of "adaptive differentiation" in the thymus; during differentiation, the form- ing repertoire of T-lymphocytes "learned" a low affinity for self MHC molecules via positive selection. This view was later countered by discovery of artifacts in underlying studies and the fact that adaptive differ- entiation could not explain direct allogeneic and allorestricted recognition phenomena. Data from experi- ments with TCR transgenic animals, individual MHC/peptide complex expression, and recipients of xeno- genic thymus glands yielded evidence of an ability to adapt to microenvironment and a low specificity of positive selection. These facts led to an alternative interpretation of MHC restriction explained, in part, by specificity of a pool of effector cells activated by primary immunization. Details of this phenomenon were defined in studies that noted differential primary structures of peptides that bound various allelic forms of MHC molecules. Here, the T-lymphocyte repertoire formed in the thymus was a result, in part, of random rearrangement of germinal sequences of TCR gene fragments. Such pre-selected repertoires were inher- ently capable of reacting with different allelic forms of MHC molecules. In contrast, MHC molecules were characterized by significant intraspecies polymorphisms; negative and positive selections were aimed at adaptation of a pre-selected repertoire to a specific microenvironment in an individual. Via elimination of autoreactive clones and sparing of a broad spectrum of specificity to potential pathogens, selection in the thymus could be considered a life-long allogeneic reaction of a pre-selected repertoire to self MHC molecules resulting in tolerance to "self," increased responsiveness to foreign MHC molecules, and cross- reactivity of the mature T-lymphocyte repertoire to individual foreign peptides plus self MHC.
Keywords: Major histocompatibility complex, MHC restriction, alloreactivity, T lymphocyte, repertoire,
Discovery of MHC restriction
specifically lysed infected targets were found in infected Dependence of the immune response and immunorec- immunocompetent mice but not in nude mice, and that ognition on MHC Class I molecules was first shown these cells were critical to disease pathogenesis. Still, in a lymphocytic choriomeningitis virus (LCMV) it was critical for them to prove that immune spleno- infection model (Zinkernagel and Doherty, 1973, cytes from other strains could kill infected cells with 1974). As later noted, the basis for an MHC restriction a respective MHC type. Using infected macrophages hypothesis was development of a test for T-lymphocyte from varied strains as targets, it was seen that immune cytotoxicity against LCMV-infected cells. Doherty T-lymphocytes of H-2b mice lysed only infected cells (using cerebrospinal liquor) and Zinkernagel (meas- from H-2b mice but had no effect on cells from hosts of uring cell cytotoxicity) saw that T-lymphocytes that a differing haplotype.
The author wishes to thank Professors Garry Abelev and Alexander Chervonsky whose helpful discussions initiated the writing of this manuscript. The author is very grateful to Professor Rolf Zinkernagel for providing some important references, and also wishes to thank Professor Alexander Shtil for being so helpful during the writing process. The work on recognition of MHC molecules by memory cells in the author's laboratory was supported by grants from the Russian Foundation for Basic Research, N-08-04-00563 and N-05-04-49793.
Address correspondence to Dr. Dmitry B. Kazansky, The Laboratory of Regulatory Mechanisms in Immunity, Carcinogenesis Institute, N. N. Blokhin's Cancer Research Center, Moscow, 115478, Russia; e-mail: kazansky@dataforce.net (Received 27 February 2008; accepted 7 August 2008)ISSN 1547-691X print/ISSN 1547-6901 online 2008 Informa UK LtdDOI: 10.1080/15476910802476708

370 D. B. Kazansky Dual specificity to MHC and virus was a pivotal finding that unveiled the role of MHC and explained T-lymphocyte responses to LCMV and other viruses. Shearer (1974) demonstrated preferential recognition of trinitrophenol (TNP)-labeled syngeneic targets by T-lymphocytes that were immune to TNP. Others proved the reproducibility of data using ectromelia and cowpox vaccine viruses (Blanden et al., 1975; Koszinowski and Ertl, 1975), H-Y antigen (Gordon et al., 1975), and minor histocompatibility antigens (Bevan, 1975); all contrib-uted to a consensus that MHC-restricted recognition was not a casual event but, rather, a general mechanism.
The MHC-restricted manner of CTL-target inter- actions was subsequently expanded to helper cells, suggesting they too could recognize antigen-induced changes in MHC Class II on B-lymphocytes and mac- Figure 1. Difference between two concepts explaining origin of
rophages. Most importantly, it became clear why MHC MHC restriction. (A) According to "adaptive differentiation" hypoth-esis, intrathymic development in contact with self-MHC (purple) molecules were polymorphic: diversity minimized the presenting self-peptides (red diamonds) results in skewed diver- opportunity for non-immunogenic molecule modifi- sity of T-lymphocytes learned to recognize external antigens (yellow cation so that immunological tolerance of a population circles) only in the context of self-MHC molecules. T-Lymphocytes became improbable. By the mid-1980s, several studies not capable to interact with self MHC/peptides complexes undergo noted that transplantation antigens encoded by MHC extensive "death by neglect." T-Lymphocytes interacting with "self" too well are subject of negative selection. (B) "Intentional priming" were antigen-presenting molecules and that they were hypothesis assumes an existence of broad peripheral repertoire recognized as complexes with antigenic peptides of T-lymphocytes. According to this hypothesis, MHC restriction is (Babbitt et al., 1985; Buus et al., 1986; Townsend et al., consequence of priming by particular combination of MHC/peptide, 1986; Maryanski et al., 1986).
allowing responses to antigenic peptides (yellow) presented by self- (purple) and foreign (green) MHC molecules.
Origin of MHC restriction: adaptive
(e.g., minor histocompatibility antigens and cow- differentiation or consequence of priming?
pox vaccine virus). This contradicted the "primary immunization model" wherein lymphocytes recog- "MHC restriction is an experimental observation of nized antigen in a complex with MHC molecules of T-lymphocyte recognition of an antigen in association any haplotype (Stockinger et al., 1980; Wagner et al., with particular MHC-encoded allelic product, but not 1981). Differences between the two models are shown with the product of another allele." This definition, pro- in Figure 1.
vided by Schwartz (1984), echoed the intense discus- The specificity of restriction of a T-lymphocyte sions of the problem at that time—with the origins of repertoire in semi-allogeneic chimerae were largely MHC restriction being the most disputed.
dependent on the time course of appearance of Defenders of so-called adaptive differentiation BM-derived antigen-presenting cells (APC) in the ("ontogenetic model of MHC restriction") based recipient thymus. In the chimerae, donor type (F ) their theory on T-lymphocyte recognition of MHC APC could be found in the recipient (P ) thymus 2 mo molecules in the body (Katz, 1977). Here, syngeneic after BM transplantation. After depletion of periph- MHC molecules restricted T-lymphocytes, as only the eral T-lymphocytes, new T-lymphocytes that migrated former were present during cell maturation. This the- from the thymus were restricted in MHC of both par- ory was supported by experiments with bone marrow ents (Longo and Schwartz, 1980). It was eventually (BM) chimeras. After transplanting BM of F hybrids confirmed that positive selection in the thymus was (after thorough removal of T-lymphocytes) into irradi- not dependent on the thymic epithelium and could ated parent (P) recipients (Bevan, 1977; Zinkernagel be regulated by other cell types (Bix and Raulet, 1992; et al., 1978; Teh et al., 1982). The resulting chimerae Hugo et al., 1993). Moreover, selection could proceed bore hematopoietic cells from the donor (F ), whereas without MHC molecules and did not require signal- other cells (including those from thymus) were of ing via a co-receptor; the only requirement was a low P1 origin. In these animals, the repertoire of mature affinity binding of TCR that caused no aggregation T-lymphocytes was narrower than in donors, and the (Takahama et al., 1994). Despite some controver- chimeras recognized mostly antigens in a context sial results from among the radiation chimerae, the with recipient MHC molecules. Recipients responded hypothesis of "adaptive differentiation in the thymus" mainly to antigens associated with their own MHC became (and still is) generally accepted.
MHC restriction and allogeneic immune response 371 MHC restriction in nude mice: lessons from
originated from the nude embryo. These mice develop animals with knocked-out recombinates
mixed chimerism in various tissues; among their and aggregation chimerae
leukocytes, CD4+, CD8+, and B220+ cells had nude hap-lotypes, whereas two CD11b+ macrophage populations The problem of MHC restriction in nude mice was thor- expressed haplotypes of each parent. The thymuses oughly investigated in RAG knockout and TCR transgenic of these chimerae bore normal cellular content and a mice (Zinkernagel and Althage, 1999). In one series of well-differentiated epithelium with RAG-10/0 haplotype. studies, nude F (H-2b x H-2d) were sublethally irradiated To rule out thymic rudiments, double staining for MHC and then received embryonic H-2b RAG-1 or H-2d SCID molecules (of RAG-10/0) and cytokeratin was performed. or H-2d RAG-10/0 thymic transplants. After 12-16 wk, the This indicated a thymus presence of non-epithelial (i.e., mice were immunized with LCMV; at Day 8, CTL restric- hematopoietic) cells with MHC molecules from a nude tion was tested and found to be restricted to thymic MHC parent. None of the chimerae had thymic rudiments with molecules. These results showed that any "bias" of MHC mature epithelial cells carrying nude haplotype.
restriction due to transplantation of thymocytes could Infection of chimerae with LCMV and subsequent CTL not be associated with specific "suppressor mecha- responses to H-2b- and H-2d-restricted peptides showed nisms," as only immuno-deficient mice thymi were used the T-lymphocyte repertoire of aggregation chimerae for reconstitution.
was restricted to MHC molecules of both parental haplo- In a second set of studies, H-2b mice were rescued types. The response was commensurate with that of wild with transplanted fully-allogeneic H-2k RAG-10/0 thymi. type mice and led to complete viral clearance from the As before, CTL activity was restricted to MHC of the re- spleen. To better characterize the CD8+ effectors' reper- cipient but not those of the thymus. The authors were toire, the cells were stained with MHC tetramers to show careful to point out that in radiation chimerae, a certain two distinct populations positive either for LCMV-GP33 amount of hematopoietic cells could survive and influ- (H-2Db) or for LCMV-NP118 (H-2Ld). Therefore, double ence positive selection. Along with the transplantation of restriction of repertoire was associated with real changes allogeneic H-2k RAG-10/0 thymi, BM cells from the same in specificity of restriction and not with cross-reactions.
immunodeficient donors were inoculated. Surprisingly, As noted above, B-lymphocytes of the chimerae specificity of recipient T-lymphocytes (recipient were chi- expressed MHC of the nude parent. This meant that in merae whose hematopoietic cells carried half-recipient aggregation chimerae, CD4+ helper cells were restricted half-donor haplotypes) was restricted to MHC molecules by non-thymic MHC molecules. Apparent contradic- of the donor and recipient and, in some cases, only to tions with the results on semi-allogeneic radiation chi- MHC molecules of the donor. The authors concluded merae were explained by an incomplete elimination of that there was an alternative (if not major) way of selec- TCR-interacting host cells after irradiation; thus, host tion and maturation of T-lymphocytes that depended on T-lymphocytes survived regardless of location in the thy- BM-derived cells.
mus or periphery. As proliferation in the thymus is very Lastly, in these studies it was seen that MHC active, these host T-lymphocytes could gain an advan- molecule expression in transplanted thymi used for H-2b tage over transplanted donor cells that must first migrate reconstitution was not necessary for restoration of the to the thymus. The aggregation chimerae are preferable T-lymphocyte repertoire. Transplantation of embryonic because populations developing on thymic and non- thymi from double Class I and II or 2-microglobulin thymic MHC are in "equal start" conditions (Martinic knockouts led to normal CTL responses to LCMV restrict- et al., 2003). In other words, early data on radiation ed to a H-2b haplotype. More surprisingly, the complete chimerae were artifacts, and the ontogenetic model of restoration of response was achieved after transplanta- MHC restriction was therefore doubtful. Most likely, this tion of thymi from xenogenic Lewis rats. Thus, the thymus model held true only to the dependence of T-lymphocyte acted mainly as an organ for differentiation, rearrange- survival on the periphery on MHC molecules. Altogether, ment, and expression of TCR genes. T-lymphocyte spe- MHC restriction of the T-lymphocyte repertoire was reg- cificity reflected expansion of the repertoire and viability ulated not as much as by the MHC haplotype of thymic of T-lymphocytes on the periphery, as well as induction epithelium, but by the haplotype of BM cells (probably, of effectors by MHC molecules on BM-derived cells.
professional APC).
Martinic et al. (2003) used aggregation allogeneic chimerae of 8-cell embryos, one of which contained Adaptive differentiation and positive
a nude homozygote and another a RAG-10/0 or SCID selection: novel approaches
homozygote. Chimerae SCID H-2d + nude H-2b and RAG-10/0 H-2b + nude H-2d were obtained; thymic Among findings underlying the ontogenetic model epithelium of the mice had the haplotype of MHC of of MHC restriction were results showing that some SCID or RAG-10/0 embryo, whereas T- and B-lymphocytes Class II molecules could increase the frequency of 372 D. B. Kazansky peripheral T-lymphocytes expressing individual V Still, experiments with transgenic TCR seldom gave regions (MacDonald et al., 1988; Blackman et al., 1989). definitive results. Indeed, some TCR were positively Furthermore, blocking individual allelic MHC products selected by MHC alleles other than the restricting one, in F hybrids with allele-specific antibodies inhibited and positive selection of certain receptors was inefficient helper and CTL responses restricted to the blocked allele even by the selecting allele (Bogen et al., 1992). Also, nar- (Marrack et al., 1988; Marusic-Galesic et al., 1989). rowing of a repertoire to CD4 or CD8 cells was far from Importantly, absence of MHC Class I prevented CD8+ absolute (Kirberg et al., 1994; Matechak et al., 1996). formation, whereas absence of MHC Class II prevented Logunova gave an interesting example of such receptors CD4+ cell development (Koller et al., 1990; Zijlstra et al., by showing TCR MM14.4 obtained in responses of trans- 1990; Cosgrove et al., 1991; Grusby et al., 1991).
genic mice with a limited peptide repertoire presented to Mice with transgenic TCR develop a great number of a syngeneic MHC Class II I-Ab molecule. Transfer of the T-lymphocytes with certain antigenic and restriction spe- transgene to wild type C57BL/6 mice led to deletion of cificity. Initial studies about positive selection of trans- T-lymphocytes with this receptor. Though the receptor genic H-Y TCR (specific for sex antigen peptide in the was initially cloned from T-lymphocyte hybridoma CD4+, context of H-2Db) (Kisielow et al., 1988; Teh et al., 1988), predominantly CD8+ cells were positively selected in mice 2C (specific for H-2Ld) (Sha et al., 1988) and AND (specif- expressing the individual complex Ab with an E chain ic for pigeon cyt-c fragment in context of I-Ek) (Berg et al., AA52-68. In mice totally lacking MHC Class II, CD4+ cells 1989; Kaye et al., 1989) allowed investigators to conclude were absent; in mice without MHC Class I, CD8+ cells that a mature T-lymphocyte with a transgenic receptor were absent. Positive selection of CD4+ T-lymphocytes could develop in the presence of a restricting MHC allele with TCR MM14.4 was observed on three alleles of MHC and absence of specific peptide. This link was clearest in Class II molecules: in BALB/c (H-2d), A bm12 mutants and mice with transgenic TCR specific to H-Y antigen. Data DM knockouts with Ab complexed with CLIP peptide of demonstrated the link between positive selection and invariant chain (li). These facts suggested degenerative MHC restriction of the repertoire, i.e., showing positive recognition of MHC molecules during positive selection.
selection of CD8+ with this TCR in the thymus of RAG0/0 Other studies of "specificity" of positive selection were H-2b/d and no selection in the RAG0/0 thymus H-2d/d.
aimed at generating transgenic mice expressing individ- It eventually became apparent the ontogenetic view- ual MHC/peptide. The net results were that limitation of point was idealized. Positive selection of CD8+ cells with the presenting peptide repertoire lowered the efficiency transgenic H-Y TCR in H-2b mice appeared associated of positive selection and presentation of endogenous with loss of CD4+ cells with the same receptor (Arsov and superantigens (Golovkina et al., 2001). Nevertheless, Vukmanovic, 1999). Studies of selection of 2C-TCR in selection of a diverse repertoire of T-lymphocytes wild type B6 mice, Kb mutants, and hosts with initially- occurred in these mice, and T-lymphocytes were expressed Ld alloantigen revealed at least five phenotypic capable of reacting on different allelic MHC molecules patterns of T-lymphocyte selection. These included: (1) (Ignatowicz et al., 1996, 1997; Chmielowski et al., 1999; positive selection (Kb and Kbm7); (2) weak positive selection Lee et al., 1999). Based on all the above, it was con- (Kbm8); (3) no positive selection (Kbm1 and Kbm10); (4) nega- cluded that positive selection of a repertoire was due to tive selection of CD8hi (Kbm3 and Kbm11); and, (5) negative degenerative recognition of endogenous MHC/peptide selection of all CD8+ cells (H-2Ld). These results showed complexes. Though efficacy can depend on variety of direct interaction of 2C-TCR with various MHC molecules peptides associated with "self" MHC molecules, positive during positive and negative selection (Sha et al., 1990).
selection cannot determine the restriction specificity of In addition, 2C TCR recognized - besides the the forming T-lymphocyte repertoire.
immunizing complex of Ld plus peptide p2Ca (LSPFPFDL) - Kbm3 plus peptide dEV8 (EQYKFYSV) and positively- Allorestricted recognition as evidence in
selecting Kb molecule associated with peptide SIYR-8 support of "priming" hypothesis
(SIYRYYGL) (Tallquist et al., 1996; Udaka et al., 1992, 1996). Recognition of peptide antigens by this receptor The most critical conclusion of the "adaptive differentia- was specific in the context of the allogeneic Ld molecule, tion" hypothesis—after experiments with semi-allogeneic whereas in the context of positively-selecting H-2Kb mol- chimerae—was that MHC restriction was a process ecule, all three peptides showed degenerative recogni- adopted by T-lymphocytes during antigen-independent tion (Tallquist et al., 1998). Moreover, positive selection differentiation in a thymus. This "narrowed" a lymphocyte of TCR could be observed in bm3 TAP0/0 mice, i.e., on repertoire to the extent that only clones specific to anti- "empty" heavy chains of Kbm3 (Kuhns et al., 2000). It was gen associated with self-MHC molecules proliferated also established that positive selection of T-lymphocyte in response to antigen. Therefore, this model presumed receptor AND could proceed on different MHC alleles that non-immune T-lymphocytes did not recognize the (Kaye et al., 1992).
antigen associated with allogeneic MHC molecules. This MHC restriction and allogeneic immune response 373 contrasted with the "priming" hypothesis that surmised tumor-associated antigens. These clones were specific that T-lymphocyte clones recognized antigen associ- to a complex of H-2Kb plus mdm-2-derived peptide; it ated with allogeneic MHC molecules. The question is noteworthy that mdm-2 is often over-expressed in arising from this collision of hypotheses was whether tumor cells. In culture, these clones selectively reacted allorestricted recognition exists.
with, and killed, melanoma and lymphoma cells - but Using the method of limiting dilutions, the frequency not normal H-2Kb-expressing dendritic cells. In vivo, of auto- and allorestricted CTL in this depleted allorestricted clones caused retardation of the growth population was determined. The frequency of precur- of melanoma and lymphoma cells in syngeneic (H-2b) sors with syngeneic restriction was ≈6 times higher than recipients (Stanislawski et al., 2001). The authors also that of precursors with allogeneic restriction. This dif- attempted to obtain allorestricted clones specific to a ference fluctuated from 2–10-fold depending on inbred cyclin D1 peptide in the context of human HLA-A2. The strain combination (Stockinger et al., 1980; Wagner et clones lysed cyclin D1-over-expressing breast carcinoma al., 1981). Similar results were observed for precursors of cells, but not Epstein-Barr-transformed lymphoblast- thymus CTL devoid of alloreactive cells and recognizing oid cells (Sadovnikova et al., 1998). Thus, allorestricted TNP derivatives in the context of syngeneic and alloge- recognition became an efficient means of breaking toler- neic MHC molecules (Stockinger et al., 1981).
ance to tumor-associated antigens and to get responses Wagner et al. (1981) were correct to suggest that a to leukemia-associated markers like WT1, CD68 and preference of the T-lymphocyte repertoire for antigen CD45 (Gao et al., 2000; Sadovnikova et al., 2002; Amrolia recognition in the context of "self" MHC could be a con- et al., 2003).
sequence of an experimental procedure and breaking An additional significant impact on the theory of allor- normal repertoire during the course of chimerism for- estriction was made in studies that identified MHC bind- mation or depletion of alloreactive cells. This was veri- ing motifs in peptides that interact with allele-specific fied in subsequent studies that determined frequencies forms of MHC molecules. Obst et al. (1998) stimulated of allorestricted clones in the repertoire of normal allo- a repertoire of T-lymphocytes H-2d with a mixture of geneic mice. Using combinations of allogeneic strains, it synthetic peptides from combinatorial libraries of pep- was seen that stimulation of CTL precursors with TNF- tides that had an MHC binding motif for interaction with modified allogeneic cells caused unusually high frequen- H-2Kb, and cells lacking TAP (to present the synthetic cies of clones that react with these CTL (1/30–1/300); peptides on APC). Incubation of the cells with peptides CTL reacting clones did not react with non-modified whose structures were optimal for binding with MHC allogeneic targets (Reimann et al., 1985a). The responses resulted in successful formation of an MHC molecule/ - of combinations of B6 and bm1 stimulators and respond- microglobulin/peptide complex and subsequent trans- ers to herpes simplex virus and TNP derivatives showed port onto the plasma membrane. Allorestricted, as well that ≈30% of reacting clones recognized their targets in as autorestricted, CTL lines obtained in response to an allorestricted manner, i.e., they did not react with such cells widely varied in their peptide specificity and non-infected or non-modified targets (Reimann et al., avidity. The authors concluded that positive selection in 1985b). Kabelitz et al. (1987) proved the existence of the context of certain MHC molecule was not required allorestricted T-lymphocytes in humans that responded for generating high avidity TCR restricted to the same to parotitis virus.
molecule, but increased the frequency of these CTL. The Restriction of allorestricted T-lymphocyte responses authors also analyzed precursors of allorestricted CTL in to MHC molecules absent in the thymus was used to peripheral blood of HLA-A2- and HLA-A3- donors. It was obtain high avidity clones capable of recognizing tumor- noted that TAP- targets that expressed these HLA (after associated antigens in patients. Indeed, normally nega- incubation with combinatorial peptide libraries bear- tive selection ablates high avidity lymphocyte clones that ing proper MHC binding motifs) induced responses. can react with self antigens of an organism (P1) in the CTL specific to these peptide libraries in the context of context of self MHC molecules (H-2x-P1). But the clones allogeneic MHC molecules comprised a major part of specific to H-2x-P1 could be presented in an allogeneic the repertoire. However, the frequency of allo-restricted P2 because negative selection deleted the clones specific CTL was two times lower than that of CTL restricted to to tumor-associated antigens in the context of "another self-MHC molecules.
self" MHC (H-2y-P2). Thus, allorestricted recognition Any links between self-MHC expression and could supposedly provide a basis to obtain clones of P2 alloreactive -restricted repertoires was subsequently specific to a combination of MHC molecule with H-2x-P1 studied. The approach used was as above, plus testing peptide (for adoptive immunotherapy).
allorestricted responses to viral and self peptides. It was noted that the closer the structures of allogeneic MHC allorestricted CTL clones of H-2d mice, thereby demon- molecule and T-lymphocyte MHC molecule were, the strating successful use of allorestricted recognition of greater the ratio of allorestricted CTL that recognize 374 D. B. Kazansky antigen peptides:CTL recognizing the allogeneic mol- but different allele-specific motifs (Falk et al., 1990, ecule independently of the peptide. As expected, the 1991a; Rotzschke et al., 1990). These studies showed that highest ratio of peptide-specific clones was found in a one could identify allele-specific sequences from among response to H-2b stimulators of mutant bm13 and bm14 the huge variety of peptides derived from one antigenic with the mutations in the H-2Db antigen-binding groove. protein (Falk et al., 1991a, 1991b).
This link could be associated with effects on the allore- These motifs formed by "anchoring" AA residues nec- active repertoire of positive selection in the thymus and essary for high affinity binding of the peptide to respec- lymphocyte survival in periphery. However, this did not tive MHC also indicated that APC expressing different prohibit recognition of peptides in an allogeneic con- MHC haplotypes would present various peptides of the text (Obst et al., 2000). Using MHC tetramer technology, same antigen. For example, influenza virus nucleopro- allorestricted T-lymphocytes that specifically recognize tein contains an epitope that binds H-2Kd in positions antigenic peptides were later isolated (Moris et al., 2001).
AA147-155 (TYQRTRALV) and H-2Db in positions AA366-
It was thus concluded that T-lymphocytes recognize 374 (MTEMNENSA). For human MHC, the epitope for
antigens in the context of MHC molecules absent during binding HLA-A2 is within AA85-94 (KLGEFYNQM),
thymocyte differentiation. The existence of lymphocytes and HLA-B27 in AA383-391 (SRYWAIRTR) (underlined
capable of recognizing antigens in the context of alloge- = anchoring [motif-forming] residues). Mechanisms of neic MHC molecules was by itself a solid argument against peptide/MHC molecule association allowed for pre- an ontogenetic origin of MHC restriction. Evidently, dicting the structure of lymphocyte peptide epitopes, positive selection in the thymus, and T-lymphocyte sur- including tumor antigens (Rotzschke et al., 1991; Wallny vival on the periphery, have low impact on formation et al., 1992; Rammensee et al., 1993). Further, these of MHC-restriction. This makes the concept of adaptive studies established a molecular basis for an association differentiation inappropriate to explain the early experi- between autoimmune diseases and certain MHC haplo- mental results of Zinkernagel and Doherty.
types (Vartdal et al., 1996; Kalbus et al., 2001; Munz et al., 2002). Finally, the ability of individual allelic products of The molecular basis of MHC restriction:
MHC molecules to bind particular peptides of the patho- MHC binding motifs
gen directly linked MHC with genetically determined immune responses to pathogens.
Can primary priming explain difficulties and contro- The Rammensee group also discovered the molecular versies in data that adaptive differentiation cannot? mechanism of MHC restriction. In initial experiments, Dependence of repertoire restriction on the replace- immunization of CBA(H-2k) mice with LCMV induced ment of host APC with donor cells in radiation chimerae CTL that recognized viral peptides with MHC H-2k bind- (Longo and Schwartz, 1980) and the simultaneous trans- ing motifs. Clearly, these specific CTL lysed infected plantation of the thymus and BM from RAG knockouts L929 cells/macrophages (H-2k) that presented the same into nude mice (Zinkernagel and Althage, 1999) led to an viral peptides. These CTL did not kill infected macro- assumption that MHC restriction was controlled at the phages of H-2d haplotype that presented totally different level of antigen presentation. Indeed, measures of spe- peptides of the virus. This was shown in analyses of im- cific functions of effector cells always required antigen munogenicity of three LCMV epitopes restricted by the priming of the naive T-lymphocytes. The "non-thymic H-2Db molecule, i.e., GP33-41 (KAVYNFATC), GP276-286
cells from BM" that partook in immune responses were (SGVENPGGYCL), NP396-404 (FQPQNGQFI). Efficacy
professsional APC, i.e., dendritic cells, B-lymphocytes, of presentation of these peptides correlated with inten- macrophages. Differing life spans of these cells after sity of the antiviral CTL response. The NP396-404 pep- lethal irradiation and different roles in immune respons- tide (bearing two anchoring residues for H-2Db binding) es might have been a source of experimental artifact showed the highest protective effect, regardless of its and misinterpretation. Conversely, it was evident that relatively low levels on APC (Gallimore et al., 1998).
primary responses (i.e., allogeneic response, reaction to bacterial superantigens) were MHC-unrestricted.
Origins of allogeneic response: direct and
Rammensee's group uncovered how APC determined restriction of effector lymphocytes. As noted in a review on MHC binding motifs in antigens (Rammensee, 1995), All transplantation antigens fall into two categories: ma- Rotzschke and Falk made this discovery in studies that jor (i.e., classical H-2-encoded MHC molecules) and mi- examined the structures of peptides that interact with nor histocompatibility antigens, i.e., other polymorphic Class I MHC molecules. The isolated peptides revealed transplantation antigens. The allogeneic MHC molecules invariant amino acid (AA) residues near the C- and are most important for rejection of a transplant. It was N- termini. Importantly, peptides bound by different seen early on that a transplant bearing foreign MHC was allelic forms of MHC Class I molecules had similar lengths rejected within 8–10 d, whereas one with alien minor

MHC restriction and allogeneic immune response 375 Figure 2. Direct and indirect recognition of allogeneic tumor cells. Rejection of allogeneic tumors represents a basic phenomenon of transplan-
tational immunology and immunogenetics, which cannot be fully explained in frames of current immunological paradigm. To destroy allogeneic
tumor cells, CTL should react to allogeneic MHC Class I molecules, not expressed on recipient's professional APC, whereas cross-priming by
self-APC should result in induction of CTL destroying self-APC presenting foreign peptides (black squares) but sparing engrafted tumor cells
expressing foreign MHC alleles and presenting unrelated peptides (black circles). In reality, in response to allogeneic tumor cells we obviously
see selective expansion of CTL directly reacting with allogeneic MHC molecules on tumor cells. Blue arrows show the direction of killing.
antigens remained viable at least 3 wk. MHC alloantigens graft proteins could be processed for presentation in induced very strong T-lymphocyte responses in culture the context of recipient MHC Class II or transferred (i.e., 1° responses), while responses to conventional into endoplasmic reticulum to be associated with antigens (i.e., ovalbumin) required pre-immunization. Class I molecules for further cross-priming of recipi- Further, alloreactive precursors were more frequent ent T-lymphocytes (Bevan, 1976; Benichou et al., 1999; than cells specific to antigens presented with self-MHC Gould and Auchincloss, 1999).
molecules. The frequency of alloreactive lymphocytes Hypothesis of adaptive differentiation was in agree- was seen to be as high as 2–5% of the total T-lymphocyte ment only with the second model, whereas primary population, whereas cells that react to soluble/viral anti- priming was in concert with both models. According to gens were normally 1:10,000 (Fischer et al., 1977).
adaptive differentiation, allogeneic recognition must be Two models explain T-lymphocyte alloantigen recog- a consequence of recognition of allogeneic peptides in nition. Direct allogeneic recognition presumed interac- the context of self-MHC of the responder. Direct inter- tion of T-lymphocyte receptor with an allogeneic MHC action with allogeneic MHC molecules can occur only molecule bound to the peptide from allogeneic APC. as a random cross-reaction of T-lymphocyte receptors After grafting, this response was mediated by migration "instructed" to react with self-MHC.
of donor APC to the recipient's lymphoid tissue. This To demonstrate indirect recognition, donor APC explained how the allogeneic response was not MHC- lysates were added to a MLR (i.e., a setting wherein direct restricted and was in concert with a dominant genetic presentation of antigen was impossible). Lysed APC of control of inducibility. Indirect allogeneic recogni-
MHC-incompatible donors induced T-lymphocyte pro- tion implied the allogeneic peptide was recognized by
liferation in the mixed lymphocyte cultures. However, T-lymphocytes bound to an MHC of the recipient and this effect was detectable only after preliminary immu- functioned in responses to minor histocompatibility nization of the recipients and not confirmed by: inhibi- antigens, and was MHC-restricted (inheritance being tion with antibodies against presenting MHC allele; use co-dominant). This mode of recognition was a result of of APC from MHC-deficient mice; or, APC from recom- presentation of allogeneic peptides derived from the binant mice that express other presenting alleles, factors graft by the recipient's dendritic cells. After engulfment, that would bolster an indirect mechanism. Moreover, no 376 D. B. Kazansky phenotyping of proliferating cells was performed due to gene products could react with MHC molecules the more a certitude that the a priori proliferating cells were CD4+ specific was thymic selection.
(Gould and Auchincloss, 1999).
Jerne's hypothesis was supported by some studies, To study responses to allogeneic Class I MHC, we even though the efficacy of thymic selection was low have used a similar system in which C57BL/10 (H-2b) (Zerrahn et al., 1997; Sebzda et al., 1999). Alloreactive mice were immunized with P815 mastocytoma (H-2d) T-lymphocytes could recognize determinants independ- cells (Kazansky et al., 1998, 1999). Re-stimulation dur- ent of the bound peptide (Mullbacher et al., 1991; Smith ing in vitro MLR was performed 2 mo later using heat- et al., 1997). Nevertheless, the bulk of data indicated that shocked stimulator splenocytes of C57BL/10 (H-2b), peptide-independent recognition was rare, and alloreac- B10.D2 or BALB/c (H-2d), and C3H (H-2k) mice. Primary tive cells recognized allogeneic MHC in association with proliferative response to dead allogeneic APC should the peptides (Rotzschke et al., 1990; Heath et al., 1991; have been absent. Dead allogeneic APC triggered Alexander-Miller et al., 1993). Dependence of alloreac- T-lymphocyte proliferation of pre-immunized recipients; tive memory CD8+ cells on MHC-bound peptides was however, in response to immunizing antigen, only CD8+ seen in our studies also. Memory CD8+ cells from B10.
cells of immune animals proliferated. Similar results D2(R101) (KdIdDb) (obtained in response to EL4 thymoma were obtained in a system with B10.D2 (R101) (KdIdDb) (KbDb)) proliferated in MLR in response to heat-shocked mice immunized with EL4 (H-2b) cells, followed by allogeneic stimulators from C57BL/6 (KbDb) wild-type re-stimulation during in vitro MLR with heated spleno- mice. Proliferation was abrogated if TAP knockout stimu- cytes from B10.D2 (R101), C57BL/6 (H-2b), and C3H lators were used. Thus, direct recognition allogeneic (H-2k) mice. It was noted that the ability to proliferate in cell depended on the peptides bound to this molecule response to dead allogeneic APC was not a consequence (Pobezinskaya et al., 2004).
of indirect recognition of the alloantigen but, rather, a Interesting and convincing data on the role of pep- specific feature of CD8+ memory cells primed by the an- tides in alloreactivity were obtained in a "single MHC/ tigen and trans-co-stimulated.
peptide" system (Kovalik et al., 2000) One study, using The tumor cells used were not professional APC, so pri- transgenic pEa mice in which all Class II MHC were rep- marily indirect recognition of the alloantigen by CD4+ cells resented by the individual complex of Ab with AA52-68 could be expected. However, only CD8+ cells proliferated. peptide of E, and DM-KO mice in which Class II mol- Primed CD8+ cells recognized the antigen directly because ecules were bound with individual CLIP peptide of the Ii proliferation of R101 mouse memory cells was blocked by invariant chain, demonstrated important mechanisms of antibody to H-2Kb and because the response was absent allogeneic and allorestricted recognition. First, both lig- if stimulation in MLR was performed with cells from TAP ands seemed "poor" stimulators of allogeneic responses, and  -microglobulin knockouts on a C57BL/6 (H-2b) supporting the "frequency of determinants" hypoth- background (Kazansky et al., 1999; Pobezinskaya et al., esis and identifying presentation of a diverse peptide 2004). Thus, even if indirect recognition of allogeneic Class repertoire for induction of intense responses. Second, I MHC was favored (immunization with non-professional T-lymphocyte hybridomas obtained in the responses to tumor APC), CD8+ cells directly interacting with foreign these "allorestricting complexes" were more sensitive to MHC Class I were a major component of the response.
stimulation with antigenic peptide; these hybridomas recognized peptide in a degenerated manner unlike hybridomas from syngeneic "autorestricted" responders. Direct allogeneic recognition: peptides or
Third, testing >500 alloreactive hybridomas showed that side chains?
the majority of alloreactive T-lymphocytes depended "Initial priming" explained alloreactivity as a conse- on the peptide (only 17% recognized this peptide spe- quence of an innate preference of T-lymphocyte recep- cifically). The authors suggested that peptides influenced tors to recognize MHC molecules of a species/a higher the allogeneic response by inducing weak conforma- density or frequency of allogeneic determinants present- tional changes in the MHC molecule -helix, and these ed by allogeneic MHC. Jerne (1971) was first to provide changes were recognized by alloreactive lymphocyte a hypothesis of evolutionary preference of TCR genes receptors. Degenerated recognition of the peptide, and according to their products' ability to interact with MHC high sensitivity to the peptide ligand, were key features of molecules of the same species. This suggested that after intrathymic elimination of self-reactive T-lymphocytes, MHC also interact with TCR; this interaction is impor- a repertoire was left that comprised of a high frequency tant for alloreactivity. CTL lyse TAP- allogeneic targets that of cells specific to all other MHC antigens. As selection express only low amounts of the "empty" heavy chains of led to enrichment of T-lymphocytes able to react with Class I MHC molecules. Moreover, in bm3 TAP knockout MHC, the TCR gene pool would be too abundant and mice, CD8+ cells formed in the thymus and accumulated "senseless" precursors produced. Thus, the more TCR in peripheral lymphoid organs, indicating that positive MHC restriction and allogeneic immune response 377 selection could occur in an absence of bound peptide peptide complex and are available for interaction with (Kuhns et al., 2000). Schneck et al. (1989a, 1989b) showed the TCR. This is why the most variable regions of the TCR that allogeneic recognition of H-2Kb by CTL was blocked CDR3 and CDR3 chains have optimal access to the by the peptide AA163-174 of the same molecule, meaning most variable component of the ligand, i.e., the peptide there was a region for binding the MHC heavy chain with (Garcia et al., 1996; Davis et al., 1998).
TCR. In our own work, peptides from C-terminal regions of A similar principle of TCR/MHC interaction was -helices devoid of MHC binding motifs for B10.D2(R101) found for allospecific TCR Bm3.3 that bind Class I H-2Kb recipients—when injected—still induced cell-mediated complexed with a naturally-processed octapeptide suppression of allogeneic responses and extended the life (pBM1:INFDFNTI). In this complex, TCR and MHC- span of allogeneic skin grafts in recipients (Brondz et al., bound peptide were linked via a CDR3 region whereas 1995). Further evidence of the interaction of TCR with in another TCR, the - and -chains had equal impact fragments of MHC molecules was demonstrated with mu- on interactions. Accordingly, only a few C-terminus tant MHC. Some individual point mutations in the MHC residues were involved in interactions. Another peculi- side -helices had no effect on the spectrum of bound arity of the complex was the very small TCR and MHC peptides, but caused intense immune responses (Falk interface; this was surprising, as the affinity of interac- et al., 1992; Grandea and Bevan, 1993). Noun et al. (1998) tion was very high. The CDR3 region of this TCR was showed that mutations in positions 62, 65, 69, 72, 152, large and was shifted from the peptide-binding groove. 163, and 166 in -helices away from the binding groove This region interacted only with Gln65 of the -helix of could be antigenic. The repertoire of peptides that bound the  domain of the MHC, whereas CDR3 consisted individual mutants did not correlate with the ability of the of nine residues that all interacted with the peptide. The mutants to evoke primary immune responses.
CDR1 and CDR2 were shifted to the N-terminus of Still, it remained unclear which AA residues were the -helix of the  -domain of the MHC molecule, i.e., critical for recognition of Class I MHC by alloreactive/ away from the peptide binding area, which abrogated autorestricted CTL. Using large panels of alloreactive and their interaction with the -helices. Thus, the position of autorestricted clones and targets that expressed mutated the ligand-bound TCR was oblique and mediated main- AA residues, it was shown that recognition by alloreactive ly by interactions with the V chain of the receptor with and autorestricted clones depended on the same residues the MHC side-chain and the peptide C-terminal part. in the heavy chains that formed common clusters of rec- These spatial considerations were relevant to the degen- ognition (Sun et al., 1995; Hornell et al., 1999). Ala muta- erative mode of peptide recognition in the allogeneic genesis-based mapping of relative energies of interaction response. For a particular TCR/MHC/peptide combina- of TCR with the MHC heavy chain revealed that ≈67% of tion, the predicted number of peptides interacting with the surface and energy in the interface between TCR and Bm3.3 TCR could increase 400-fold (Reiser et al., 2000).
MHC molecules belonged to interaction of the receptors Nevertheless, evidence supports a general degen- with the Class I heavy chain (Manning et al., 1998). These erative recognition of MHC/peptide complexes by all data indicated that alloreactivity not be explained solely TCR (Eisen, 2001). Usually, a detailed analysis of cross- by differences in the peptide repertoire presented by reactivity of individual TCR reveals additional MHC or various MHC. Side -helices also play an important role peptide ligands capable of interacting with receptors of being capable of direct interaction with the TCR.
interest. Cross-reactivity was found in our studies of an MHC molecules present "self" and "alien" peptides to alloreactive MCC-1 clone of CD8+ memory cells obtained T-lymphocytes. The groove MHC-peptide is directed to in a response to an allogeneic H-2Kb molecule. This clone the extracellular milieu and is a plane formed by -helices could be activated by the immunizing antigen as well and the peptide. Topologically, interactions within each as in a response to H-2Dd(Ld) and H-2Dq(Lq). However, TCR/MHC/peptide complex are similar to those in all lengths of the CDR3 and - chains of its TCR were others, i.e., TCR is oriented diagonally to external sur- similar (Pobezinskaya et al., 2004). Most likely, a degen- face of MHC/peptide complex. Spatially, the CDR1 and erative manner of recognition is an important trait of the CDR2 of the TCR -chains are localized near the peptide immune response that allows T-lymphocytes to recog- N-terminus, whereas similar parts of the -chain are nize an enormously wide variety of MHC-bound pep- positioned near the C terminus. CDR1 and CDR2 chains tides; the specificity is sufficient to discriminate between encoded by the V region interact mainly with MHC AA "self" and "foreign".
residues. The third region in the TCR is most variable and It can thus be concluded that there are no critical determines the complementary interaction CDR3-MHC. differences in recognition of a peptide in the context of The regions of TCR CDR3 and CDR3 are oriented to syngeneic or allogeneic MHC. Both types of interaction the center of the TCR/MHC/peptide and interact mainly can induce highly-specific immune responses to indi- with the central portion of the peptide. Several residues vidual MHC/peptide complexes and are efficient in rec- in the peptide form the external surface of the MHC/ ognizing other combinations. Nevertheless, responses to 378 D. B. Kazansky allogeneic MHC/peptide complexes are characterized and most HLA-DR-peptide conjugates might be sterically by a large number of degeneratively recognizing clones optimized coordination sites for Ni. In the complexes, Ni that cross-react with other MHC by interacting with their may effectively bridge the TCR-chain to His81 in most -helices. These clones supposedly appear since nega- DR. Thus, analogous to super-antigens, Ni may link TCR tive selection does not eliminate them.
to MHC in a peptide-independent manner. However, unlike super-antigens, Ni requires idiotypic (i.e., CDR3- Role of MHC in immunotoxicology:
determined) TCR AAs. This novel TCR-MHC linkage might recognition of xenobiotics
explain the high frequency of Ni-reactive T-lymphocytes in humans (Gamerdinger et al., 2003).
In light of the increased understanding of the MHC and its CBD, a granulomatous lung disorder caused by work- role(s) in normal host immune responses, several studies site beryllium (Be), is characterized by accumulation of have sought to determine the bases for T-lymphocyte- Be-specific CD4+ T-lymphocytes. Depending on genetic mediated phenomena like contact hypersensitivity susceptibility and the nature of exposure, CBD occurs in (CHS) and allergic contact dermatitis (ACD) in response up to 20% of exposed workers. Susceptibility has been to small chemical compounds, chromium and nickel associated with particular HLA-DP alleles, especially agents, as well as chronic lung beryllium disease (CBD) those possessing a negatively-charged Glu residue at in response to beryllium ions.
AA69 of the -chain. The basis for this association lies Low-molecular chemicals with an intrinsic potential to in the ability of these HLA-DP to bind and present Be covalently modify proteins are classified as haptens. Many to pathogenic CD4+ cells. Large numbers of effector are strong inducers of T-lymphocyte-mediated CHS, and memory, Be-specific CD4+ lymphocytes are recruited to hapten-specific lymphocytes are known to interact with the lung and secrete T 1-type cytokines upon Be recog- hapten-modified MHC-associated peptides. In contrast nition. A presence of circulating Be-specific CD4+ cells to these classical haptens, nickel (Ni) ions do not form directly correlates with severity of lymphocytic alveolitis. covalent bonds to proteins, but become caught in revers- As such, CBD serves as an important model of immune- ible coordination complexes. Some T-lymphocytes may mediated organ destruction. The findings related to CBD react to such Ni complexes on the MHC/peptide-surface, have implications for studies of autoimmune diseases, akin to what happens with common haptens. In other in particular, those with unknown inciting antigens and cases, Ni ions may activate lymphocytes by cross-linking inaccessible target organs (Amicosante and Fontenot, their receptors to MHC independent of the nature of the 2006; Newman, 2007).
peptide (Thierse et al., 2004, 2005). The MHC restriction Drug-induced hypersensitivity reactions have been element in Ni-reactive T-lymphocytes (ANi-2.3) was des- explained by the hapten concept, i.e., a compound is ignated DR52c. A series of experiments established that too small to be recognized by the immune system. After the functional ligand for these lymphocytes was a pre- the drug is covalently bound to an endogenous protein, formed complex of Ni bound to a combination of DR52c the hapten-carrier complex (larger modified protein) is and a specific peptide that generated in B-lymphocytes immunogenic to B- and T-lymphocytes. Consequently, (but not in fibroblasts or any other antigen processing- an immune response (to the drug) with very heteroge- deficient cells). In addition, ANi-2.3 recognition of this neous clinical manifestations develops. In recent years, complex was dependent on His81 of the MHC -chain, evidence has shown that not all drugs need covalently suggesting a role for this AA in Ni binding to MHC. Lu bind to the MHC-peptide complex in order to trigger et al. (2003) proposed that a general model for Ni recogni- an immune response. Rather, some may directly and tion was one in which His81 and two AA from the NH - reversibly bind to immune receptors like the MHC or terminal part of the MHC bound peptide-coordinated TCR, thereby stimulating the cells similar to a pharma- Ni which, in turn, interacts with some portion of the V cological activation of other receptors. This concept has CDR1 or CDR2 region.
been termed "pharmacological interaction with immune In another study using the T-lymphocyte clone SE9, po- receptors," the (p-i) concept.
tential Ni contact sites in the TCR and the restricting histo- While the exact mechanism is still a matter of debate, compatibility leukocyte antigen (HLA)-DR structure were non-covalent drug presentation clearly leads to activa- identified. The specificity of this HLA-DR-favoring V22/ tion of drug-specific T-lymphocytes by various agents V17+ TCR was primarily due to its -chain. Ni reactivity (e.g., lidocaine, sulfamethoxazole, lamotrigine, car- was neither dependent on APC protein processing nor bamazepine, p-phenylendiamine, etc.). In some patients affected by the nature of HLA-DR-associated peptides. with drug hypersensitivity, such a response may occur However, SE9 activation by Ni did depend on Tyr29 in within hours upon first exposure to the drug. Thus, the CDR1, an N-nucleotide-encoded Tyr94 in CDR3, and reaction may not be due to a classic primary response but, a conserved His81 in the HLA-DR -chain. This indicated rather, be mediated by stimulating existing pre-activated, that labile non-activating complexes between SE9 TCR peptide-specific lymphocytes cross-specific for the drug. MHC restriction and allogeneic immune response 379 By this, certain drugs may circumvent checkpoints in repertoire; this frequency was similar to that after immune activation imposed by antigen processing and selection. This indicated the innate predisposition of presentation mechanisms; this may explain the peculiar TCR to interact with MHC. Genes coding for TCR were nature of many drug hypersensitivity reactions (Pichler evolutionary designed in a way such that their products et al., 2006).
bind predominantly with MHC side -helices; this is par- As with indirect and direct responses to grafted tissues, ticularly true for V-segment CDR1 and CDR2 regions.
the role of chemically-modified peptides (in the context These results were surprising. Indeed: (1) preferential of MHC molecules) as well as direct influence on TCR/ interaction of TCR with the MHC is not a consequence MHC interactions in these reactions can be clarified. In of positive selection in a thymus; (2) the T-lymphocyte a structure of Class I domains recognized by TCR, AA repertoire is primarily specific to all variants of classic residues have been identified that are invariant even in MHC molecules, presuming a coordinated evolution of evolutionary—very distant species. Their location on three independent genetic loci (/, , and MHC); and, 3D-structure models indicates that in structure-forming (3) alloreactivity and MHC restriction can be a sequelae function, as a rule, they are located in contact sites of this innate specificity. Yang et al. (2002) estimated between -helices and -sheets. Studies of combinatorial there were four combinations of peptides with the H-2Kb homology between Class I and II molecules have identi- that induced auto- and allorestricted responses in three fied a fragment located in a "kink"-region of both Class I mouse strains.
(AA154-164) and -chains of Class II molecules (AA63-73, Responders were primed in vitro with stimulators A-molecules; AA 69-79, E molecules) at which a spectra loaded with peptides, followed by evaluation of frequen- of "allowed" AA substitutions significantly coincide. Thus, cies of peptide specific CTL. Three out of four peptides this region could play a role as "anchor" for interactions induced responses restricted by self-MHC better than with TCR, providing the capability for the latter to distin- by alien MHC, but differences were only 3–5-fold. The guish MHC from other molecules (Kazanskii et al., 2004). fourth peptide induced auto- and allorestricted CTL Importantly, point mutations here result in well-known with equal efficacy. Titration of peptides showed that Kbm1 and A bm12 molecules capable of inducing vigorous high avidity CTL were present among the auto- and allogeneic responses in wild-type C57BL/6 mice.
allorestricted CTL. The authors concluded that narrow- Although knowledge of the details of interaction ing the repertoire to a preferential recognition of antigens between small xenobiotics and MHC molecules is im- in the context of self-MHC (which can be expected from perfect, it can be anticipated that chemical modification positive selection in thymus) was minor. Further analy- or acquiring reversible coordination complexes in/near sis of lectin-stimulated maturation of thymocytes from a kink-region will result in highly immunogenic forms mice deficient in MHC showed that the number of Kb- of these molecules and increased risk for development restricted CTL among these lymphocytes was similar to of autoimmune and allergic diseases. The involvement of the number of allorestricted CTL. Thus, MHC-restricted His81 and Glu69 in Class II -chains into recognition of recognition of peptides was innate and imminent for a Ni and Be ions may suggest this idea (Gamerdinger et al., T-lymphocyte repertoire, and this recognition did not 2003; Lu et al., 2003; Newman, 2007).
require thymic selection on MHC molecules.
As early as 1971, Jerne postulated the genetic predis- Back to Jerne's hypothesis
position of the repertoire for MHC recognition, i.e., "anti-body specificity is determined by structural V-genes that Is it reasonable that the ability of T-receptor repertoires code for AA sequences of variable regions on antibody to interact with MHC are genetically determined? Two polypeptide chains." The present hypothesis proposes groups have seen that non-selected lymphocyte receptor that a host's germ-cells carry a set of V-genes determin- repertoires had an innate capability to recognize MHC in ing combining sites of antibodies directed against a com- the thymus (Merkenschlager et al., 1997; Zerrahn et al., plete set of a given class of histocompatibility antigens of 1997). One demonstrated that 20% of thymocytes rec- the host species. Though this hypothesis is 37 years old, ognize MHC prior to positive and negative selection, as its importance remains great.
CD69 activation marker was expressed upon recognizing cells. The other used T-lymphocytes from mice that did What is really going on?
not express MHC, i.e., DP lymphocytes (immature) with a receptor repertoire not positively or negatively selected Much data appeared to not fit the hypothesis of for MHC. Using monoclonal antibodies against TCR/ ontogenetic origin of MHC restriction. Among the prob- and CD4, maturation of the lymphocytes was induced lems encountered has been: experiments on which the in fetal thymic organ cultures. Analysis of TCR spe- hypothesis was founded have been criticized; results in cificity revealed a high frequency of clones that reacted transgenic TCR hosts have been largely refuted; and, spe- with allogeneic MHC in a pre-selected T-lymphocyte cificity of restriction by T-lymphocytes was associated 380 D. B. Kazansky not with the thymus, but with cells originating in the BM i.e., antigen presentation. However, the reason could be (minor impact from microenvironment and periphery deduced based on a hypothesis that pinpointed MHC survival). As a result, an "initial priming" hypothesis molecule alloantigenic traits. Indeed, changes in alloan- emerged that based itself on the critical role of a primary tigenic "image" of the molecule would change the char- immune response to a given MHC/peptide combination. acter of negative selection of the repertoire; this would Due to this priming, a portion of the lymphocyte reper- provide an opportunity to rescue individual clones that toire arose that was specific to recognition of particular respond to the pathogen.
MHC/peptide complexes, i.e., specificity was dictated The proposed hypothesis seemed to both reconcile by antigen-presenting cell. Limiting this specificity by transplantation immunology with MHC restriction and thymic "bringing-up" to given MHC/peptide complexes explain alloreactivity, and provided a foundation for the resulted in a variable repertoire of T-lymphocytes capa- phenomena, i.e., interaction of repertoire with histo- ble of reacting with allogeneic MHC molecules.
compatibility molecules. Adaptive differentiation failed Identification of MHC-binding motifs in antigenic to explain alloreactivity, and even genetic control of peptides provided a structural basis for explanation of allogeneic reactions and MHC-restricted recognition was the origin of MHC restriction in terms of "initial prim- considered differentially. The ability to induce a specific ing." Combinatory peptide libraries proved the existence allogeneic response was inherited as a dominant trait, of a broad repertoire of allorestricted T-lymphocytes whereas an ability to induce MHC-restricted responses and revealed an insignificant role for positive selection was co-dominant. To researchers of MHC-restricted in narrowing repertoires down to autorestricted clones. recognition, allogeneic effects were distracting; geneti- Taking into account that adaptive differentiation could cally defined hosts were needed to avoid these. It is thus not provide explanations to phenomena of allorestricted understandable that allogeneic phenomena were put responses and direct allogeneic recognition, it was time aside; this situation changed after discovery of allor- to admit that an ontogenic origin of MHC restriction, though still predominant in immunology textbooks, was Jerne's hypothesis solved the enigma of dominant misleading. The hypothesis also tried to explain allore- inheritance of alloantigenicity by linking V gene struc- activity as cross-reactivity with "self." But for what reason tures and an innate predisposition of a repertoire to rec- were "cross-reactive" alloreactive clones not deleted ognize transplantation antigens. A precise provision of during thymic negative selection? Were cross-reactions Jerne was confirmed by discovery of MHC peptide pres- more pronounced than specific ones? The most obvious entation in studies that showed that allelic forms of the answer was no. Logic suggested that "the reaction of the molecules presented different peptides. Other studies repertoire to foreign transplantation antigens was spe- proved the critical role of a broad peptide repertoire in the cific, whereas recognition of peptides in the context of intensity of allogeneic responses. Overall, this hypothesis self MHC was a "cross-reaction." stated that "the high intensity of an allogeneic response Loss of some specificities potentially useful for was explainable by two non-exclusive peculiarities of responses to pathogens was inevitable and created an T-lymphocyte recognition: (1) a genetically,determined Achilles' heel in the organism being attacked. Because ability of a repertoire to interact with the entire spectrum MHCs were highly polymorphic and their allelic forms of a species' MHC; and, (2) specificity of negative selec- presented different peptides from the same protein, tion that maintained the ability of a repertoire to respond this vulnerability was individual within a species. This to peptides in the context of allogeneic MHC molecules." was why selection of virus variants for ability to escape Apparently, the major problem for the immune immunological attack in one organism would not rescue system was to avoid transplantation conflict in a host. a variant from the immune system of a different host. Indeed, receptors of adaptive immunity "see" self- Thus, MHC polymorphism created a safety net that al- antigens more frequently than pathogens. In any case, lowed slowly-evolving vertebrata to survive even in the existence of a potentially dangerous system in the host presence of quickly evolving pathogenic organisms.
could be no less a factor in the evolution of its immune The traits of the immune system used to be consid- system than the pathogen. Thus, MHC-restricted recog- ered in the context of co-evolution with pathogenic nition could develop not as much in the struggle with microorganisms. By this, polymorphism among MHCs pathogenic microorganisms, but in inhibiting reactions would mean the variability of only those AA residues with "self." By this, restriction of immune reactions by responsible for peptide presentations. However, the several types of recognized molecules would be helpful. majority of variable residues localized in TCR binding MHC have allowed the immune system to redirect these regions and had no impact on peptide binding specifi- reactions to short peptides containing AA substitutions city; nevertheless, these variable residues were necessary not presented in the responding organism. On the other for MHC alloantigenicity. The reason for polymorphism hand, they have allowed the responding organism to was unclear, considering the traditional role of MHC, form specific central tolerance to self, not involving in MHC restriction and allogeneic immune response 381 this process a huge diversity of conformations created by Benichou, G., Valujskikh, A., and Heeger, P. S. 1999. Contributions of other proteins. As such, alloreactivity can be, not only a direct and indirect T-cell alloreactivity during allograft rejection in mice. J. Immunol. 162:352–358.
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Source: http://kazansky1.narod.ru/works/369.pdf


RA Journal of Applied Research Volume 1 Issue 1 Pages-18-43 November -2014 ISSN (e): Appli Importance of Physicochemical Properties In Drug Discovery. (Review Article) Kapadia Akshay Bhupendra Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga (East), Mumbai.


Koffer 1. Carle, Eric: Die kleine Raupe Nimmersatt, Gerstenberg, Bilderbuch, 2014.25 Exemplare Auch kleine Raupen können großen Hunger haben. Deshalb macht sich die Raupe Nimmersatt auf die Suche nach etwas zu essen - und wird fündig. Sie frisst sich von Montag bis Sonntag Seite für Seite durch einen Berg von Leckereien, bis sie endlich satt ist. Nun ist die Zeit gekommen, sich einen Kokon zu bauen, und nach zwei Wochen des Wartens schlüpft aus ihm ein wunderschöner Schmetterling. Die Kleinsten spielen mit der Kleinen Raupe Nimmersatt und sind fasziniert von den gestanzten Raupenfresslöchern. Etwas größere Kinder entdecken mit ihr die Wochentage, Früchte, Zahlen und die Metamorphose in der Natur.