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The Journal of Immunology, 2003, 171: 4006-4010.
Copyright © 2003 by The American Association of Immunologists

MHC Class I Gene Conversion Mutations Alter the CD8 T Cell Repertoire

Matthew S. Block, Michael J. Hansen, Virginia P. Van Keulen and Larry R. Pease1

Department of Immunology, Mayo Medical and Graduate Schools, Mayo Clinic Rochester, Rochester, MN 55905


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
MHC class I molecules are highly polymorphic within populations. This diversity is thought to be the result of selective maintenance of new class I alleles formed by gene conversion. It has been proposed that rare alleles are maintained by their ability to confer resistance to common pathogens. Investigation has focused on differences in the presentation of foreign Ags by class I alleles, but the majority of peptides presented by class I molecules are self peptides used in shaping the naive T cell repertoire. We propose that the key substrate for the natural selection of class I gene conversion variants is the diversity in immune potential formed by new alleles. We show that T cells compete with each other for niches in the thymus and spleen during development, and that competition between different clones is dramatically affected by class I mutations. We also show that peripheral naive T cells proliferate preferentially in the presence of the class I variant that directed T cell development. The data argue that class I gene conversion mutations dramatically affect both the development and the maintenance of the naive CD8 T cell repertoire.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Class I Ag-presenting molecules from the MHC are the most polymorphic proteins known in mammalian populations. Diversity is conserved across multiple species and is present in all classical class I loci. In particular, >23 different class I isoforms were identified among the three classical class I loci, H2-K, -D, and -L, in a survey of 10 inbred mouse strains (1), while at least 615 class I isoforms are present among the human homologues HLA-A, -B, and -C (2). Furthermore, the ratio of replacement to silent mutations within portions of class I loci is higher than would be predicted in the absence of selection, indicating that new class I variants are selectively maintained in populations (3). Variation among class I alleles is not uniform throughout the molecules, but is concentrated on those residues that are involved in peptide binding; therefore, selection for class I diversity focuses on peptide binding residues (3).

Whereas polymorphism in many genetic loci appears to be generated by point mutation, variation in class I is formed by templated mutation or gene conversion (4, 5). In both mice and humans, new variant genes have been shown to be hybrids of two or more parental class I genes (4, 5, 6, 7). Newly arisen alleles that differ from parental alleles by only a single gene conversion event have been selectively maintained in human populations (6, 7), suggesting that the selective process that diversifies class I distinguishes and selects gene conversion variants.

Because of the importance of class I in the cell-mediated immune response, it has been hypothesized that new class I variants are selectively maintained because they possess a high propensity to generate a beneficial immune response to pathogens (8). Under this hypothesis, pathogens evolve most efficiently to evade the immune responses generated by the class I molecules that are most common in a population. Evasion of immune responses generated by the most common alleles does not necessarily aid the pathogen in evading responses generated by rare alleles, so individuals with rare alleles have an advantage in pathogen immunity compared with individuals possessing common alleles. Enhanced immunity confers a survival advantage to individuals with rare class I alleles.

Class I molecules play two distinct roles in CD8 T cell immunity, either or both of which might impact the immune response to pathogens. First, class I molecules present self-peptides to developing thymocytes in the thymus and to naive CD8 T cells in the secondary lymphoid organs. By presenting self-peptides, class I molecules play a critical role in both the selection and maintenance of the CD8 T cell repertoire (9, 10). Secondly, class I molecules bind to antigenic peptides and present them during activation and targeting of CD8 T cells during an immune response. Thus, gene conversion-generated polymorphisms might impact immunity to pathogens either by impacting CTL activation and targeting and/or by altering CD8 T cell repertoire formation. The consequences of MHC gene conversion mutations to Ag presentation and T cell recognition are well known (11). Ag-specific changes in immune potential have also been reported (12, 13).

The detection of differences in the naive T cell repertoire is made difficult by the fact that individuals possess ~107–108 different T cell clones, making identification and comparison of individual clones impractical. Characterization of T cell repertoires by V{beta} usage or spectratyping has revealed aberrations in the T cell repertoire associated with autoimmunity (14), but has not demonstrated differences between healthy individuals that differ from one another by gene conversion mutations. It has, however, been demonstrated that if the repertoire of naive T cells is reduced to one dominant clone by generation of a TCR-transgenic animal, different gene conversion variants lead to different thymic selection outcomes of the transgenic clone (15, 16). This suggests that repertoire formation might differ among gene conversion variants.

Under normal circumstances, multiple T cell clones with varying specificities mature simultaneously. When the number of developing cells exceeds the homeostatic limit for a given cell type, only those cells with the most optimal selection properties survive; this is known as competition (17). Competition during thymic selection was demonstrated by Freitas et al. (18). Briefly, bone marrow chimeras were made bearing bone marrow cells from two Db-restricted TCR-transgenic mice. The prevalence of T cells bearing either TCR transgene was measured during different stages of T cell development. Changes in the relative frequency of T cells from the transgenic donors during T cell maturation indicate that the two Db-restricted T cell clones competed with each other for prevalence in the T cell repertoire. Competition among naive CD8 T cell clones has also been observed during peripheral homeostasis (19). Here, we use the principle of intercellular competition to determine whether gene conversion mutations in class I alter the CD8 T cell repertoire.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice

2C TCR{alpha}{beta} transgenic mice were originally described by D. Loh (20) and have been maintained at the Mayo Clinic. B6 mice (C57BL/6J), bm3 class I mutant mice (C57BL/6J-H2bm3/Eg), bm5 class I mutant mice (C57BL/6Kh-H2bm5/KhEg), bm8 class I mutant mice (B6.C-H2bm8), bm14 class I mutant mice (B6.C-H2bm14/By), OT-1 TCR{alpha}{beta} transgenic mice (C57BL/6-TgN(TcrOva)1100Mjb), LCMV TCR{alpha}{beta} transgenic mice (B6;D2-TgN(TcrLCMV)327Sdz), B6Thy1.1 marker congenic mice (B6.PL-Thy1a/Cy), and B5Ly5.1 marker congenic mice (B6.SJL-Ptprca Pep3b/BoyJ) were obtained from The Jackson Laboratory (Bar Harbor, ME). All experiments were performed in compliance with institutional and National Institutes of Health guidelines for animal care and use.

Bone marrow transplants

Bone marrow transplant recipients were given 900 rad of whole body irradiation using a 137Cs irradiator (J. L. Shepherd and Associates, San Fernando, CA) 4–8 h before transplantation. Donor bone marrow cells were isolated as described previously (21). Isolated bone marrow cells were depleted of T cells using anti-CD4 and anti-CD8 magnetic beads as recommended by the manufacturer (Miltenyi Biotec, Auburn, CA). A total of 5 x 106 T cell-depleted bone marrow cells were transplanted i.v. into each recipient. For mixed bone marrow transplants, 2.5 x 106 cells from each donor were transplanted. Recipient mice were given 1 g/L of tetracycline (Fort Dodge Animal Health, Fort Dodge, IA) in their drinking water for 1 wk before and 2 wk following bone marrow transplantation.

Adoptive transfer of splenocytes

Adoptive transfer recipients were given 600 rad of whole body irradiation using a 137Cs irradiator (J. L. Shepherd and Associates) 24–30 h before transfer. Donor splenocytes were isolated, and mixtures of splenocytes from two donors were labeled with 1 µM CFSE (Molecular Probes, Eugene, OR) for 10 min at 37°C, diluted in PBS as previously described (10). Labeled splenocytes (2 x 106) were transferred i.v. into recipients.

Flow cytometry

Abs to CD4, CD8, V{alpha}2, V{beta}5, V{beta}8, Thy1.1, Thy1.2, Ly5.1, and Ly5.2 were purchased from BD PharMingen (San Diego, CA). The anti-2C clonotypic mAb 1B2 (22) was conjugated to PE using a Phycolink kit from Prozyme (San Leandro, CA). Cells were incubated with 5 µg/ml of mAb for 20 min on ice. Reagents were diluted in HBSS containing 10 g/L of BSA and 0.2 g/L of sodium azide. After incubation, cells were washed three times in HBSS/BSA/azide. Cells were fixed in 2% paraformaldehyde. FACS analyses were performed by the Mayo Flow Cytometry Core Facility on a FACSCaliber (BD Biosciences, Franklin Lakes, NJ), and data, collected as log10 fluorescence, were analyzed using CellQuest (BD Biosciences).

Statistical analysis

Paired data were analyzed using Student’s paired t test. Unpaired data were analyzed using Student’s unpaired t test. A value of p < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Kb-restricted T cells compete with each other for niches in the T cell repertoire

To determine whether Kb-restricted T cell clones compete with each other similarly to Db-restricted clones, we reconstituted lethally irradiated B6 mice with a mixture of bone marrow cells from two Kb-restricted TCR-transgenic donors: 2C (20) and OT-1 (23). We then measured the relative presence of 2C- and OT-1-derived cells in the bone marrow, thymus, and spleen. OT-1 cells seeded the bone marrow far more efficiently than 2C cells (data not shown), and this difference in seeding efficiency was reflected in the relative frequency of immature CD4/CD8 double-positive (DP) 2 cells in the thymus, where cells bearing the 2C TCR make up only 3.2 ± 0.3% of DPs (Fig. 1). However, as the two clones mature, 2C cells become significantly more prevalent; they make up 9.3 ± 1.0% of CD8 single-positive (SP) thymocytes, and 15.3 ± 2.4% of CD8-SP cells in the spleen (Fig. 1). This indicates that as the T cells mature in B6 hosts, cells with 2C TCR out-compete cells with OT-1 TCR for efficient selection and maintenance, thus demonstrating that Kb-restricted T cells, similar to Db-restricted T cells, compete during selection and maintenance.



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  		FIGURE 1. Kb-restricted T cells compete for niches in the T cell repertoire. C57BL/6 mice were transplanted with a mixture of bone marrow from 2C and OT-1 TCR-transgenic donors. The percentage of cells bearing the 2C TCR (1B2 clonotypic mAb; {blacksquare}) and the OT-1 TCR (anti-V{alpha}2 and anti-V{beta}5 mAbs; ) are shown for thymic DP cells, thymic CD8-SP cells, and splenic CD8-SP cells. Results shown are the mean ± SEM (n = 16), with paired Student’s t tests comparing data for 2C.

 
Class I gene conversion variants alter competition between class I-restricted T cells

To determine whether polymorphisms in class I alter competition among TCRs for niches in the T cell repertoire, we transplanted mixtures of bone marrow from TCR-transgenic donors into both B6 recipients and recipients bearing spontaneous gene conversion mutations in class I. We transplanted a mixture of bone marrow from OT-1, a Kb-restricted transgenic donor, and from LCMV (24), which is restricted to Db. The gene conversion variant recipients we used were derived from B6 parents and bore mutations in either the K locus (bm3 (25), bm5 (26), and bm8 (27)) or in the D locus (bm14 (28)). Each gene conversion variant differed from the parental class I molecule by one or more amino acid residues in the peptide binding site. If bone marrow from a single transgenic donor was used (OT-1 or LCMV), a high percentage (>80%) of T cells in both thymus and spleen of the recipient bore the donor transgenic TCR, regardless of the class I background of the recipient (data not shown). This indicates that each recipient is capable of positively selecting both OT-1 and LCMV T cells. However, if a mixture of bone marrow cells from the two donors was transplanted, the resulting repertoire of transgenic T cells was heavily dependent on the recipient’s class I alleles. B6 and bm5 recipients generated a mature repertoire of ~60% OT-1 and ~30% LCMV. By contrast, bm3 and bm8 recipients heavily favored LCMV over OT-1 (>75% LCMV), whereas bm14 recipients’ repertoires were dominated by OT-1 and had <10% of mature splenocytes bearing the LCMV TCR (Fig. 2). This indicates that competition among developing T cells is dramatically altered by gene conversion-based polymorphisms in class I.



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  		FIGURE 2. Class I gene conversion variants alter competition between class I-restricted T cells. C57BL/6 and class I gene conversion variants bm3, bm5, bm8, and bm14 were transplanted with a mixture of bone marrow from OT-1 and P14 TCR-Tg donors. The percentage of splenic CD8-SP cells bearing the OT-1 TCR (anti-V{alpha}2 and anti-V{beta}5, {blacksquare}) and the P14 TCR (anti-V{alpha}2 and anti-V{beta}8; ) are shown. Results shown are the mean ± SEM (n = 8, 2, 4, 3, and 4 for B6, bm3, bm5, bm8, and bm14, respectively), with unpaired Student’s t tests comparing data for OT-1.

 
B6 and bm5 mice have significantly different T cell repertoires

While competition between OT-1 and LCMV TCR-transgenic T cells revealed T cell repertoire differences between parental B6 animals and mutant bm3, bm8, or bm14 animals, no significant differences were seen between B6 and bm5 mice. This mirrors previous findings in TCR-transgenic mutants, where B6, bm5, and the related mutant bm7 are identical in positive selection of the transgenic TCRs (15, 16). Because it fails to show demonstrable repertoire differences from B6 in cases where one or two dominant clones are identified, bm5 is a stringent test case for the hypothesis that class I gene conversion mutations lead to CD8 T cell repertoire differences.

To test whether bm5 mice generate polyclonal T cell repertoires that are significantly different from those of B6 mice, we exploited the principle of T cell competition, this time in the setting of homeostatic proliferation in a lymphopenic host. When an individual is rendered lymphopenic by irradiation, drug treatment, or Ab treatment, surviving T cells in that individual will proliferate to repopulate the T cell compartment of that individual (10). To measure competition between mature T cells that had been generated in B6 and bm5 mice, we mixed mature splenocytes that had developed in either B6 or bm5. We then transferred the mixture of mature cells into B6 or bm5 recipients that had been sublethally irradiated to render them lymphopenic. If the T cell repertoires generated by B6 and bm5 are the same or very similar, we would expect cells from either donor to compete with equal efficiency in either a B6 or a bm5 recipient. On the other hand, if B6 and bm5 generate significantly different T cell repertoires, then we would expect B6-derived donor cells to have a competitive advantage in a B6 recipient; bm5-derived T cells would have an advantage in a bm5 recipient.

Ordinarily, if mature T cells are transferred to a recipient with class I alleles that differ from those of the donor, graft-vs-host disease will ensue. To prevent graft-vs-host disease from occurring as well as to distinguish cells from B6 and bm5 donors, we performed mixed bone marrow transplants in which we transplanted a mixture of cells from either B6Thy1.1 and bm5 donors or B6Ly5.1 and bm5 donors into B6 and bm5 recipients, respectively (Fig. 3A). After allowing T cells in these bone marrow chimeras to develop for 8 wk, we transferred mixtures of splenocytes from B6 chimeras (Thy1.1-marked) and bm5 chimeras (Ly5.1-marked) into B6 and bm5 recipients (Fig. 3A). We labeled the mixtures of splenocytes with CFSE before transfer to track their proliferation. Seven days after transfer, we compared competition between B6 cells tagged with the Thy1.1 and Ly5.1 markers in the B6 and bm5 recipients, as measured by the number of cells from each donor and by the ability of the cells from each donor to proliferate and dilute CFSE. As an internal control, we normalized the data obtained for CD8 T cells to those obtained for CD4 T cells; since class II is identical between B6 and bm5, we would expect that competition between CD4 cells would be identical in either recipient (Fig. 3A). CD8 T cells from B6 donors had a significant numerical advantage in B6 recipients compared with bm5 recipients, in which bm5-derived cells had an advantage (Fig. 3B). Consistent with this observation, B6-derived cells proliferated significantly more in B6 recipients than in bm5 recipients (Fig. 3B). These data indicate that CD8 T cells from B6 and bm5 donors compete differently in B6 and bm5 recipients; therefore, the CD8 T cell repertoires generated in these mice are significantly different from one another.



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  		FIGURE 3. B6 and bm5 mice have significantly different T cell repertoires. A, Experimental design. B6Thy1.1 and bm5, or B6Ly5.1 and bm5 bone marrow were transplanted into lethally irradiated B6 and bm5 recipients, respectively. Eight weeks after transplant, splenocytes were isolated from bone marrow transplant recipients, mixed, labeled with CFSE, and transferred i.v. into sublethally irradiated B6 and bm5 recipients. One week after adoptive transfer, splenocytes were isolated from adoptive transfer recipients and assayed by flow cytometry. Data obtained from B6 adoptive transfer donors (Thy1.1) were compared with those obtained from bm5 donors (Ly5.1), and data for CD8 T cells were normalized by dividing by data for CD4 T cells within an adoptive transfer recipient. B, Results. The ratio of the number of CD8 T cells from B6 ({blacksquare}) and bm5 () adoptive transfer donors (after normalization for CD4 T cells) is shown as well as the level of CFSE staining in cells of B6 ({blacksquare}) and bm5 () origin. Results shown are the mean ± SEM (n = 6), with paired Student’s t tests comparing data for B6 recipients with that for bm5 recipients.

 
Several independent experiments comparing B6 repertoires with those of both bm5 and bm3 mice have all demonstrated significant repertoire differences, as measured by differences in cell number and/or proliferation in B6 and mutant recipients (Table I). Importantly, if the B6Thy1.1 and B6Ly5.1 cells develop in different B6 bone marrow chimeras, rather than B6 and bm5 chimeras, respectively, there is no significant difference in competition between the two marked cells in B6 vs bm5 recipients (Table I). This indicates that the differences seen in competition between the marked cells is due to differences between the repertoires generated by B6 and bm5 animals, rather than to some intrinsic difference between the two types of marked cells. Thus, gene conversion mutations confer significant differences on the T cell repertoire, as measured by competition in lymphopenic hosts.


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  		Table I. Summary of peripheral competition experimentsa

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Diversity in class I peptide binding residues appears to confer a selective advantage upon an individual. If selection of diversity is immune based, then class I variants could drive selection either by altering which subset of potential antigenic peptides is bound and presented during an immune response or by changing the immune potential of an individual by altering the repertoire of CD8 T cells that are available to respond during an infection. Several studies have indicated that class I alleles have different Ag binding profiles (29, 30); however, because pathogens are antigenically complex, even alleles that do not confer resistance or that lead to a suboptimal response are often capable of binding to peptides derived from a pathogen (31). Therefore, we hypothesized that selection for diversity might be due to differences in the T cell repertoire.

We have demonstrated that gene conversion-generated polymorphisms in class I lead to changes in competition among T cell clones, both during maturation in the thymus and during homeostatic expansion in the periphery. Using TCR-transgenic bone marrow donors, we have shown that different alleles of class I impact the relative frequency of competing T cell clones, indicating that the efficiency of competition is altered by class I variants. When normal repertoire generation is not bypassed by a TCR transgene, the number of clones is too numerous, and the frequency of individual clones is too rare for individual TCRs to be identified. However, we used bone marrow transplantation and adoptive transfer of allotype-marked cells to identify T cells not by their TCR structure, but by which class I molecules mediated their generation. Using this strategy, we demonstrated that T cells arising from different class I variants compete differently in different hosts. This observed change in competition indicates significant differences in the T cell repertoires generated by different class I molecules. Generation of the T cell repertoire begins in the thymus, where those thymocytes that bind with the most appropriate affinity to class I self-peptide complexes are positively selected and complete maturation (9). The repertoire is also shaped by continual competition in the periphery (19). Because of this, the difference in the competitive fitness of peripheral T cells from different class I variants may indicate alterations in positive selection, peripheral homeostasis, or both.

Each of the class I mutants used in this study differs from the parental Kb or Db molecule by one to four amino acids. Although the mutant mice were not selected in nature, the mutations they bear represent polymorphisms present in wild mice. While some of the mutations, such as bm8, have been shown to have significant effects on Ag binding (32), others, such as bm5, have not. The mutant K allele Kbm5 differs from the parental Kb only at one amino acid, position 116 (Kb = Y, Kbm5 = F) (26). Residue 116 is positioned in the floor of the peptide binding groove, with the side chain pointing toward the bound peptide but not making direct contact with the peptide (33). Furthermore, B6 and bm5 mice reject skin from one another weakly, if at all (34), and Abs (35, 36, 37) and T cell clones (35, 38, 39) that recognize Kb generally recognize Kbm5. Given the similarities between the two molecules, it is perhaps not surprising that Kb and Kbm5 have not been found to differ significantly in their ability to bind to antigenic peptides (35, 39), nor did they differ in mediating competition between OT-1 and LCMV (Fig. 2). On the other hand, position 116 is among the most highly polymorphic in both mice and humans, with at least six naturally occurring amino acids in mice (1) and at least eight in humans (40). Furthermore, in human patients substitutions at position 116 significantly increase the risk of graft-vs-host disease (41), indicating that position 116 substitutions affect the immune response. Thus, if selection drives diversity, then polymorphisms in position 116 would be expected to play a major role in selection. If we hypothesize that selection of the T cell repertoire drives diversification of the class I loci, then we must also hypothesize that polymorphisms in position 116 (such as bm5) will affect selection of the T cell repertoire. We indeed found that bm5 mice have significantly different CD8 T cell repertoires from B6, indicating that conservative mutations in position 116 can alter the T cell repertoire.

Residue 116 is not predicted to make direct contact with the bound peptide (33), yet even subtle substitutions in position 116 clearly affect the T cell repertoire. There are several possible mechanisms to explain these changes. The side chain of position 116 interacts indirectly with the bound peptide through a bridging water molecule (33); changes in the hydrogen bond status of the bound water molecule could alter peptide binding. Alternatively, substitutions in position 116 may indirectly impact the repertoire of peptides bound by altering interactions between class I heavy chains and Ag processing machinery. Mutations in position 116 in human class I molecules have been shown to impact interactions between class I and TAP, tapasin, and calreticulin (42, 43). Furthermore, variant alleles differ in their ability to load peptides optimally (44). Thus, position 116 mutations may affect peptide binding and the T cell repertoire either by altering the Ag-binding site and/or by altering the process of peptide loading.

We have shown that gene conversion mutations in class I produce dramatic effects on competition between CD8 T cells, and therefore, the variants produce significantly altered T cell repertoires. This finding suggests that alterations in the CD8 T cell repertoire are responsible for altered immunity between gene conversion variants, and that selection of variants occurs due to changes in the T cell repertoire.


   Footnotes
 
1 Address correspondence and reprint requests to Dr. Larry R. Pease, Department of Immunology, Mayo Medical and Graduate Schools, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. E-mail address: pease.larry{at}mayo.edu Back

2 Abbreviations used in this paper: DP, double positive; SP, single positive. Back

Received for publication June 11, 2003. Accepted for publication August 14, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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