AUTHOR=Migalska Magdalena , Węglarczyk Kazimierz , Dudek Katarzyna , Homa Joanna TITLE=Evolutionary trade-offs constraining the MHC gene expansion: beyond simple TCR depletion model JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2024 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1240723 DOI=10.3389/fimmu.2023.1240723 ISSN=1664-3224 ABSTRACT=

The immune system is as much shaped by the pressure of pathogens as it is by evolutionary trade-offs that constrain its structure and function. A perfect example comes from the major histocompatibility complex (MHC), molecules that initiate adaptive immune response by presentation of foreign antigens to T cells. The remarkable, population-level polymorphism of MHC genes is assumed to result mainly from a co-evolutionary arms race between hosts and pathogens, while the limited, within-individual number of functional MHC loci is thought to be the consequence of an evolutionary trade-off between enhanced pathogen recognition and excessive T cell depletion during negative selection in the thymus. Certain mathematical models and infection studies suggest that an intermediate individual MHC diversity would thus be optimal. A recent, more direct test of this hypothesis has shown that the effects of MHC diversity on T-cell receptor (TCR) repertoires may differ between MHC classes, supporting the depletion model only for MHC class I. Here, we used the bank vole (Myodes=Cletronomys glareolus), a rodent species with variable numbers of expressed MHC genes, to test how an individual MHC diversity influences the proportions and TCR repertoires of responding T cell subsets. We found a non-linear relationship between MHC diversity and T cell proportions (with intermediate MHC numbers coinciding with the largest T cell proportions), perhaps reflecting an optimality effect of balanced positive and negative thymic selection. The association was strongest for the relationship between MHC class I and splenic CD8+ T cells. The CD8+ TCR richness alone was unaffected by MHC class I diversity, suggesting that MHC class I expansion may be limited by decreasing T cell counts, rather than by direct depletion of TCR richness. In contrast, CD4+ TCR richness was positively correlated with MHC class II diversity, arguing against a universal TCR depletion. It also suggests that different evolutionary forces or trade-offs may limit the within-individual expansion of the MHC class II loci.