title: 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-E(b), due to a monomorphic Eα(k) transgene that pairs with the endogenous I-Eβ(b) 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.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid, Box 8118, St. Louis, MO 63110, United States.
authors.forename: Peggy P
authors.initials: PP
authors.lastname: Ni
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid, Box 8118, St. Louis, MO 63110, United States.
authors.forename: Yaming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid, Box 8118, St. Louis, MO 63110, United States. Electronic address: pallen@wustl.edu.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Allen
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian; D005802:Genes, MHC Class II / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019076:Transgenes
chemical_list: D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen
keywords: Alloreactivity; Autoimmunity; CD4(+) T cells; Class II MHC; Viral infection