TY - JOUR
T1 - Both positive and negative effects on immune responses by expression of a second class II MHC molecule
AU - Ni, Peggy P.
AU - Wang, Yaming
AU - Allen, Paul M.
N1 - Funding Information:
This work was supported by the National Institutes of Health grant AI24157 (P.M.A.) and by the American Heart Association grant 10PRE3050039 (P.P.N.). The authors thank T. Hansen and G. Morris for critical review of the manuscript; C. David for the B6.E + mice; G. Wu for assistance with the EAE model; M. Colonna for advice on the LCMV infections; D. Kreamalmeyer for maintenance of the mouse colony; and the Speed Congenics Facility of the Rheumatic Diseases Core Center (Washington University School of Medicine) under National Institutes of Health Award Number P30AR048335.
PY - 2014/11
Y1 - 2014/11
N2 - 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.
AB - 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.
KW - Alloreactivity
KW - Autoimmunity
KW - Class II MHC
KW - Viral infection
UR - http://www.scopus.com/inward/record.url?scp=84904257340&partnerID=8YFLogxK
U2 - 10.1016/j.molimm.2014.06.024
DO - 10.1016/j.molimm.2014.06.024
M3 - Article
C2 - 25016574
AN - SCOPUS:84904257340
SN - 0161-5890
VL - 62
SP - 199
EP - 208
JO - Molecular Immunology
JF - Molecular Immunology
IS - 1
ER -