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The Journal of Immunology, 2000, 164: 1695-1698.
Copyright © 2000 by The American Association of Immunologists

MHC Polymorphism Can Enrich the T Cell Repertoire of the Species by Shifts in Intrathymic Selection

Ruben Dyall*, Ilhem Messaoudi*,{ddagger}, Sylvia Janetzki{dagger} and Janko Nikolic-ugic1,*,{ddagger}

* Laboratory of T Cell Development and {dagger} Swim Across America Laboratory, Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and {ddagger} The Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10021


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The murine class I molecule H-2Kb and its natural gene conversion variant, H-2Kbm8, which differs from H-2Kb solely at 4 aa at the bottom of the peptide-binding B pocket, are expressed in coisogenic mouse strains C57BL/6 (B6) and B6.C-H-2bm8 (bm8). These two strains provide an excellent opportunity to study the effects of Mhc class I polymorphism on the T cell repertoire. We recently discovered a gain in the antiviral CTL repertoire in bm8 mice as a consequence of the emergence of the Mhc class I allele H-2Kbm8. In this report we sought to determine the mechanism behind the generation of this increased CTL diversity. Our results demonstrate that repertoire diversification occurred by a gain in intrathymic positive selection. As previously shown, the emergence of the same Mhc allele also caused a loss in positive selection of T cell repertoire specific for another Ag, OVA-8. This indicates that a reciprocal loss-and-gain pattern of intrathymic selection exists between H-2Kb and H-2Kbm8. Therefore, in the thymus of an individual, a new Mhc allele can select new T cell specificities, while abandoning some T cell specificities selected by the wild-type allele. A byproduct of this repertoire shift is a net gain of T cell repertoire of the species, which is likely to improve its survival fitness.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Major histocompatibility complex (Mhc)-encoded class I molecules present cytosolically processed peptides to CTL (1). In the thymus, class I molecules shape the CTL repertoire via positive (reviewed in Ref. 2) and negative (reviewed in Ref. 3) selection. MHC class I molecules are the most polymorphic molecules in mammals (4), and some of them arose in laboratory mice as recently as several decades ago (5). Upon emergence of a new Mhc allele, the CTL responsiveness of the individual bearing it is likely to be modified. This modification could occur because the new class I allele would bind new peptides and would thus enable the existing CTLs to respond to them. The fact that the Mhc polymorphism can be found selectively concentrated in the peptide-binding regions of the {alpha}1 and {alpha}2 domains, where it affects the spectrum and conformation of MHC-bound peptides (6, 7, 8, 9), supports this possibility. Many cases of the MHC-linked immune response (Ir) gene control were shown to operate via differential Ag presentation (Refs. 10, 11, 12, 13 , and reviewed in Ref. 14), providing indirect evidence in favor of this mechanism. Alternatively, the new class I allele could select new CTL precursors in the thymus that were not selected by the parental class I molecule. The role of this mechanism remains speculative (15), or, when experimental, indirect and limited to losses in positive (reviewed in Ref. 14) or negative (13, 16) selection.

A mutation in the four clustered amino acids at the floor of the class I H-2Kb molecule separates the parental strain C57BL/6 (B6, H-2b) and the coisogenic strain B6.C-H-2bm8 (bm8, H-2bm8) (17). We recently showed that this polymorphism results in a reciprocal loss-and-gain pattern of T cell reactivities. In this paper we demonstrate that this difference in reactivities is caused by a shift in intrathymic selection. H-2Kbm8 cannot positively select CTLs specific for OVA-8, which are readily selected by H-2Kb, but is able to select HSV-8-specific repertoire that is broader and better in protecting against the viral challenge than the one selected by H-2Kb. Therefore, in an individual, naturally selected Mhc variation produces shifts in intrathymic selection of T cells, so that some new CTL specificities are gained and some of the existing ones sacrificed. The byproduct of this mechanism is the diversification of the immune repertoire and an increase of the defensive fitness of the species.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice, immunization, restimulation and 51Cr-release assay

C57BL/6 (B6, H-2b, Thy-1.2; the National Cancer Institute breeding program, Frederick, MD), B6.C-H-2bm8 (bm8, H-2bm8, Thy-1.2), B6.PL-thy-1a/Cy (B6.PL, H-2b, Thy-1.1), and their F1 offspring (The Jackson Laboratory, Bar Harbor, ME, via Dr. J. Sprent, The Scripps Research Institute, La Jolla, CA) were used at 6–10 wk. Peptide and virus immunization, restimulation, and 51Cr-release assay were as described (18). Briefly, 7 days following the virus or peptide/adjuvant immunization, spleen cells were restimulated with irradiated (30 Gy) syngeneic spleen cells coated with 10 µg/ml HSV-8 (SSIEFARL) peptide, and the CTL activity was assessed 5 days later in a standard 51Cr-release assay exactly as described (19). For Vß utilization, CTL lines were derived by three successive weekly restimulaitons on peptide-coated spleen cells, thus ensuring that all CD8 T cells will be specific for the HSV-8 peptide.

Flow cytofluorometric analysis

mAb F23.1 ({alpha}Vß8) was purified and conjugated to FITC in our laboratory. Other Abs were purchased from PharMingen (San Diego, CA). Day 7 restimulated CTL were stained with FITC-conjugated Vß-specific mAbs and counterstained with an anti-CD8-PE mAb. Staining, data acquisition, and analysis were as described (19). Vß utilization was normalized to the perentage of TCR{alpha}ß+CD8+ cells (>90% in all samples), and significance was determined using the paired Student’s t test.

Bone marrow irradiation chimera

These were produced as described (20), except that the recipient’s CD8+ cells were eliminated by two i.p. injections of 100 µg of the anti-CD8 mAb 53.6.7 on days -1 and 1 relative to irradiation. Briefly, B6 or bm8 animals were supralethally irradiated (11 Gy) and reconstituted by the injection of 5 x 106 T cell-depleted (B6.PL x bm8)F1 bone marrow cells i.v. To examine the ability of Kb and Kbm8 molecules present on the thymic radioresistant (epithelial) cells to positively select HSV-8-specific repertoire, chimeric mice were immunized 12 wk later with HSV-8 (whole virus or HSV-8/TM), and the CTL activity was tested as above. At the time of testing, donor-derived cells were found to make up >95% of chimera T cells, as judged by flow cytofluorometric analysis. Furthermore, all chimera responded to HSV immunization, providing an internal control for immunocompetence.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Functional and structural gain in anti-HSV-8 CTL diversity in bm8 mice

Immunization of B6 mice with intracellularly loaded OVA or the live HSV or with OVA257–264 and HSV glycoprotein B498–505 peptides elicits CTL responses directed against naturally processed, H-2Kb-restricted epitopes SIINFEKL (OVA-8) and SSIEFARL (HSV-8), respectively (Refs. 18, 21 and Table IGo). An MHC coisogenic mouse strain, bm8, responded to HSV-8 (Dyall et al.,2 and Table IGo) but not to OVA-8 (19, 20, 22). The nonresponsiveness to the latter Ag is caused by the lack of intrathymic pos-itive selection (Ref. 20 ; and see Table IIIGo). H-2Kbm8 differs from H-2Kb by three ß-strand substitutions, Y22->F, M23->I, and E24->S, and by a loop substitution, A30->N (17), located on the floor of the peptide binding site (8, 9). Two of them (Y22->F and E24->S) have the potential to directly affect peptide binding, but neither of the four has solvent accessibility and thus are predicted not to interact directly with the TCR (23, 24, 25, 26). Other parts of H-2Kbm8, including its TCR-contacting residues, are identical to those of H-2Kb (9, 17).


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  		Table I. bm8 CTL can recognize HSV on both H-2Kb and H-2Kbm8 a

 

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  		Table III. The broader anti-HSV CTL repertoire in bm8 mice is the consequence of an H-2Kbm8-mediated gain in intrathymic positive selection

 
We recently showed that anti-HSV-8 B6 and bm8 CTLs differ in their ability to recognize closely related peptide:MHC complexes. B6 anti-HSV-8 CTLs did not recognize HSV-8:H-2Kbm8 (Ref. 19 , footnote 2, and Table IGo). By contrast, bm8 anti-HSV-8 CTL lines strongly cross-reacted on HSV-8:H-2Kb (Table IGo). Therefore, immunization of bm8 mice with HSV-8 induced cross-reactive CTLs that could not be induced by the same immunogen in B6 animals. The same CTL lines were tested for TCR Vß utilization by flow cytofluorometric analysis. (All CTL lines for this and other analyses were tested after three in vitro restimulations using HSV-8 peptide-coated irradiated syngeneic spleen cells. This duration of in vitro CTL culture was selected because it allows establishment of pure CD8+ CTLs, without substantial skewing of the CTL repertoire toward clonal populations.) As previously reported (27), B6 mice invoked a highly restricted TCR Vß repertoire, dominated by Vß10+ and Vß8+ CTL (Table IIGo). By contrast, bm8 anti-HSV-8 (Table IIGo) and (B6 x bm8)F1 anti-HSV-8 (data not shown) CTL repertoires were more diverse, displaying frequent Vß3, -4, -5, -6, -9, -11, and 13 usage, in addition to Vß8 and -10. Thus, in response to HSV-8, CTL from bm8 mice expressed both broader functional reactivity and more diverse Vß utilization than those from B6 mice. (Experiments with established bm8 CTL lines restimulated for >8 in vitro cycles also revealed occasional utilization of Vß5, -6, -9, and -12. Furthermore, analysis of HSV-8-specific clones from B6 and bm8 mice confirmed both the difference in specificity and the difference in clonal diversity: of 18 B6 clones, all were monospecific, 11 were Vß10+ and 4 were Vß8+, with Vß7 and -5 being used by the other three; of 28 bm8 clones, 67% were cross-reactive, and they expressed TCRs using 8 Vß families, with Vß10 being the most frequent in 7, or >25% of them (I. Messaoudi, J. Le Maoult, and J. Nikolic-Zugic, in preparation).)


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  		Table II. TCR Vß utilization by HSV-8-specific CTL lines from B6 and bm8 mice1

 
This difference in Vß utilization was not the property of naive B6 and bm8 TCR repertoires because naive B6 and bm8 CD8 thymocytes (data not shown) and splenic T cells (Table IIGo) demonstrate an indistinguishable pattern of Vß utilization. Furthermore, the difference was specific for the anti-HSV-8 response, because H-2Kk alloantigen-specific B6 and bm8 CTLs (obtained by stimulation with B10.A(4R) T cells that do not express class II molecules and thus differ from the responder cells solely at the H-2K locus) (Table IIGo), as well as the anti-VSV-8 response restricted by H-2Kb/H-2Kbm8 (footnote 2) also utilized the same array of Vßs. These results simultaneously argue against massive, superantigen- or similar tolerogen-induced alterations in the available TCR repertoire of B6 mice.

TCR repertoire shift by positive intrathymic selection

The aim of this study was to investigate the mechanism responsible for this increased functional diversity. The differences between the B6 and bm8 anti-HSV-8 CTL repertoire could be caused by differential Ag presentation, positive or negative intrathymic selection, and/or peripheral tolerance. H-2Kb and H-2Kbm8 bind (19) and present (Table IGo) HSV-8 with comparable efficacy, and the thermostability of the HSV-8:H-2Kb and HSV-8:H-2Kbm8 complexes at the cell surface is virtually indistinguishable (19). These results ruled out differences in Ag binding and presentation as an explanation for different CTL repertoire. Negative intrathymic selection and peripheral tolerance are dominant traits (3, 28) and, if responsible for the observed differences, would be expected to delete the cross-reactive CTLs and eliminate CTLs bearing Vß3, -4, -11, and -13 in (H-2Kb x H-2Kbm8)F1 mice and in [(H-2Kb x H-2Kbm8)F1->H-2Kbm8] bone marrow irradiation chimera. However, both types of animals generated CTLs that recognized both HSV-8:H-2Kb and HSV-8:H-2Kbm8 and displayed a Vß utilization pattern similar to bm8 CTLs (Tables 2–4; data not shown), arguing against negative selection of the HSV-8:H-2Kbm8-specific CTLs by H-2Kb.

Intrathymic positive selection was examined in [(B6 x bm8)F1 -> parent] bone marrow irradiation chimera. In these animals, radioresistant thymic epithelium bears parental H-2 molecules that then positively select the T cell repertoire from among the immature F1 thymocyte precursors (2). Following positive selection in the thymus, selected CTLs can interact with Ags presented by either H-2Kb or H-2Kbm8, both of which are expressed by the F1 peripheral APC (20, 29), and both of which bind and present the HSV-8 peptide efficiently (Table IGo, Ref. 19). Upon immunization with the immunodominant OVA-8 and HSV-8 peptides/adjuvant, these chimera confirmed a previously observed (20) defect in the positive selection of anti-OVA-8 CTLs by H-2Kbm8 (Table IIIGo, Expt. 1). Both chimera types positively selected HSV-8-specific CTLs, as evidenced by vigorous lysis of HSV-8-coated F1 cells (Table IIIGo, Expt. 1). However, F1 CTLs selected by H-2Kbm8 (F1->Kbm8) recognized both HSV-8:H-2Kb and HSV-8:H-2Kbm8, whereas the same F1 cells selected by H-2Kb (F1->Kb) recognized only HSV-8:H-2Kb (Table IIIGo, Expt. 2). Immunization with the whole virus yielded the same results (Table IIIGo, and data not shown), ruling out possible artifacts of peptide immunization. Furthermore, the anti-HSV-8 CTL selected by the H-2Kbm8 thymus utilized a broader array of TCR Vß genes, compared with the one selected by H-2Kb (Table IVGo). We conclude that positive intrathymic selection most likely dictates both the functional and the Vß TCR diversity of the anti-HSV-8 CTLs.


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  		Table IV. TCR Vß utilization by HSV-8-specific CTL lines from F1->B6 and F1->bm8 mice1

 
Concluding remarks

These results demonstrate a shift in intrathymic selection between H-2Kb and H-2Kbm8 molecules. H-2Kb, but not H-2Kbm8, can select CTLs specific for OVA-8. In a reversal of roles, H-2Kbm8 selects anti-HSV-8 CTLs that are not selected by H-2Kb. Our results (Ref. 20) and this manuscript) strongly suggest that the difference in selection occurs via positive selection. Formally, we have to allow the theoretical possibility that negative selection might be indirectly implicated (e.g., owing to an insufficient density of H-2Kb:peptide complexes in the F1->P thymus because of "hemizygosity"). However, the exquisite sensitivity of the immune system to even the low abundance of deleting Ags and an outright lack of experimental support for the hemizygosity mechanism render this possibility unlikely. Preliminary experiments using mixed (B6 + bm8)->P chimeras and thymus grafting also support this conclusion (data not shown).

The bm8 mutation occurred approximately within the last 40 years (about 200 generations, assuming 5 generations/year) (5). Our recent results indicate that shifts in CTL repertoire occurring as the consequence of this mutation can have palpable consequences for the defense of the individuum, inasmuch as bm8 mice were better equipped to combat the HSV infection than the parental strain, B6. In a typical experiment, when challenged with the same dose of HSV virus, B6 and bm8 mice demonstrated 3.3% (1/30) and 63.3% survival (19/30), respectively.2 Clearly, the reciprocal nonresponsiveness of bm8 mice to OVA-8 is not evolutionary important, but a "hole" in the CTL repertoire directed against a relevant pathogen, owing to the above shift in selection, would produce negative survival effects as well. During evolution, positive and negative intrathymic selection (as well as peripheral tolerance) have come to a balance. For each species, it is believed that an optimal number of the MHC class I molecules was selected to ensure a diverse and functional immune system (6, 7, 15). Indeed, it was calculated that increasing the number of expressed MHC alleles beyond a certain limit leads to a net loss of repertoire by negative selection (15). It is then likely that, for an optimal (and constant) number of MHC molecules expressed, any new allele would lead mainly to qualitative changes in the T cell repertoire of an individuum, since the sum of selected T cell specificities per organism would roughly remain constant (15). Our results demonstrate that the byproduct of shifts in intrathymic T cell selection is an increase in the sum of the selected T cell specificities of the species. Thus, intrathymic selection on newly arising MHC variants can play an important role in enabling the species to more effectively combat a wider spectrum of pathogens and increase its chance for survival.


   Acknowledgments
 
We thank Jing Xu for technical assistance, Dragana Nikolic-ugic for flow cytometric analysis, Dr. S. Vukmanovic (New York University Medical Center, New York) for the critical comments on the manuscript, and Dr. S. Silverstein (Columbia University, New York) for the HSV virus. This work was supported in part by the PEW Charitable Trust, the MSKCC Society, and the DeWitt Wallace Fund. R.D. was a Thomas Jefferson predoctoral fellow of the African-American Institute during a part of this work. J.N.- was a PEW scholar in the Biomedical Sciences.


   Footnotes
 
1 Address correspondence and reprint requests to Dr. Janko Nikolic-ugic, Memorial Sloan-Kettering Cancer Center, Box 98, 1275 York Avenue, New York, NY 10021. E-mail address: Back

2 R. Dyall, I. Messaoudi, S. Janetzki, J. LeMaoult, and J. Nikolic-ugic. Diversification of the antiviral cytotoxic T lymphocyte (CTL) repertoire and enhancement of antiviral resistance by Mhc class I polymorphism. Submitted for publication. Back

Received for publication September 13, 1999. Accepted for publication November 24, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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