Both positive and negative effects on immune responses by expression of a second class II MHC molecule
Both positive and negative effects on immune responses by expression of a second class II MHC molecule
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DOI：
10.1016/j.molimm.2014.06.024
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发表时间：
2014-11-01
影响因子：
3.6
通讯作者：
Allen, Paul M.
中科院分区：
文献类型：
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作者：
Ni, Peggy P.;Wang, Yaming;Allen, Paul M.
令人费解的是，为什么脊椎动物表达的主要组织相容性复合体 (MHC) 分子数量有限，而从理论上讲，拥有更多的 MHC 分子会增加呈现的表位数量，从而增强胸腺选择和 T 细胞对病原体的反应。任何积极的影响都可能被限制 T 细胞库的消极选择所抵消或抵消。我们假设 MHC 数量的限制是由于表达额外的 MHC 产生的负面后果。我们比较了 B6 小鼠 (I-A(+)) 和 B6.E+ 小鼠 (I-A(+)、I-E+) 之间的 T 细胞反应，后者由于与内源 I-E beta(b) 链配对的单态 E α(k) 转基因而表达第二类 II MHC 分子 I-E-b。首先，B6.E+ 胸腺和脾脏中的初始 T 细胞 V beta 库发生了改变，可能介导 T 细胞反应性的不同结果。尽管 B6 和 B6.E+ 对鸡蛋清溶菌酶 (HEL) 蛋白免疫的反应仍然相似，但其他免疫模型产生了差异。对于病毒感染，T 细胞反应的质量发生了微妙的改变，B6.E+ CD4(+) T 细胞产生的某些细胞因子减少。在同种异体反应中，B6.E+ T 细胞反应显着减弱。最后，我们观察到 B6.E+ 小鼠对实验性自身免疫性脑脊髓炎 (EAE) 的易感性显着增强。这与 nTreg 细胞百分比下降相关，支持 Treg 对负选择表现出不同敏感性的概念。总而言之，我们的数据表明，表达额外的 II 类 MHC 可以产生多种效应，更严重的自身免疫为限制 MHC 分子的表达提供了令人信服的解释。 (C) 2014 Elsevier Ltd. 保留所有权利。
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 E alpha(k) transgene that pairs with the endogenous I-E beta(b) chain. First, the naive T cell V beta 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. (C) 2014 Elsevier Ltd. All rights reserved.