Both positive and negative effects on immune responses by expression of a second class II MHC molecule

Abstract

It is perplexing why vertebrates express a limited number of Major Histocompatibility Complex (MHC) molecules when theoretically, having a greater repertoire of MHC molecules would increase the number of epitopes presented, thereby enhancing thymic selection and T cell response to pathogens. It is possible that any positive effects would either be neutralized or outweighed by negative selection restricting the T cell repertoire. We hypothesize that the limit on MHC number is due to negative consequences arising from expressing additional MHC. We compared T cell responses between B6 mice (I-A+) and B6.E+ mice (I-A+, I-E+), the latter expressing a second class II MHC molecule, I-Eb, due to a monomorphic Eαk transgene that pairs with the endogenous I-Eβb chain. First, the naive T cell Vβ repertoire was altered in B6.E+ thymi and spleens, potentially mediating different outcomes in T cell reactivity. Although the B6 and B6.E+ responses to hen egg-white lysozyme (HEL) protein immunization remained similar, other immune models yielded differences. For viral infection, the quality of the T cell response was subtly altered, with diminished production of certain cytokines by B6.E+ CD4+ T cells. In alloreactivity, the B6.E+ T cell response was significantly dampened. Finally, we observed markedly enhanced susceptibility to experimental autoimmune encephalomyelitis (EAE) in B6.E+ mice. This correlated with decreased percentages of nTreg cells, supporting the concept of Tregs exhibiting differential susceptibility to negative selection. Altogether, our data suggest that expressing an additional class II MHC can produce diverse effects, with more severe autoimmunity providing a compelling explanation for limiting the expression of MHC molecules.

Evidence that MHC I-E dampens thyroid autoantibodies and prevents spreading to a second thyroid autoantigen in I-Ak NOD mice

“…H2 h4 mice, TgAb levels are significantly lower and TPOAb are virtually absent on a NaI-diet. Consistent with our observations, a recent study observed that expressing additional I-E molecules in C57BL/6 mice limited autoimmunity ( 32 ).…”

Effective NY-ESO-1–specific MHC II–restricted T cell receptors from antigen-negative hosts enhance tumor regression

“…This is in line with our finding of significantly more CD8 + T cells in the testing (33). The presence of more MHC molecules in the thymus is thought to lead to a higher number of T cells affected by negative selection and thereby fewer alloreactive T cells (34). Thus, the reason that there were more alloreactive ABabDR4-derived TCRs in comparison to human-derived TCRs in this study may be that the ABabDR4 mouse expresses only one MHC II molecule.…”

In vitro and in vivo evaluation of lactic acid bacteria of aquatic origin as probiotics for turbot (Scophthalmus maximus L.) farming

“…On the other hand, the major histocompatibility complexes (MHC) I and II present antigenic peptides on cell surface for recognition by cells of the immune system, as T lymphocytes and NK cells [68]. They play a central role in the immune response and in the recognition of nonself antigens, therefore their expression can affect to the infection/ disease susceptibility [69]. In our work, turbot bathing with Lc.…”