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

Abstract

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.

Distinct and Non-Overlapping T Cell Receptor Repertoires Expanded by DNA Vaccination in Wild-Type and HER-2 Transgenic BALB/c Mice

“…Two mechanisms may be postulated. Recruitment of TCR repertoire is critically determined by both a competition between T cells to access the APCs (35,36) and precursor frequency (37,38). Thus, it may be suggested that the TCRs belonging to the repertoire activated by immunization in BALB/c mice (namely those carrying the 138-bp V␤18-J␤1.6, 113-bp V␤18-J␤1.6, and 113-bp V␤20-J␤2.7 rearrangements) have a high precursor frequency that prevents activation of other, low frequency T cells.…”

Erbb2 DNA Vaccine Combined with Regulatory T Cell Deletion Enhances Antibody Response and Reveals Latent Low-Avidity T Cells: Potential and Limits of Its Therapeutic Efficacy

“…The low avidity of these cells may underlie their cryptic behavior. Although low-avidity cells can escape thymus selection (10,32), their access to Ag is possibly limited by competition with T cells of higher avidity in BALB/c mice (33)(34)(35). Alternatively, it can be suggested that the cryptic CD8 + repertoire is positively selected only in BALB-neuT mice as an effect of thymic expression of rErrb2 (15).…”

Inability of bm14 Mice to Respond to Theiler’s Murine Encephalomyelitis Virus Is Caused by Defective Antigen Presentation, Not Repertoire Selection

“…Previously, we demonstrated that class I polymorphisms cause significant changes in the T cell repertoire (16). We showed that when repertoires generated by closely related alleles respond to an Ag presented by one of the alleles, the repertoires respond differently, as indicated by their tetramer-binding preferences; however, these differences did not dictate whether a recipient could respond to TMEV.…”

“…It has been shown previously that gene conversion mutations can affect presentation of antigenic peptides (15). Recently, we have shown that gene conversion mutations also cause dramatic changes in the T cell repertoire, thereby impacting immune potential (16). T cell repertoire differences have been implicated in the altered ability of gene conversion variants to respond to viral infection (13); however because repertoire selection and Ag presentation are both mediated by class I, it is difficult to distinguish differences in these functions.…”

“…Gene conversion mutations have been shown to alter both Ag presentation (15) and the T cell repertoire (16,37). However, neither of these changes is likely the direct substrate for selection of class I diversity.…”