Myelin oligodendrocyte glycoprotein induces incomplete tolerance of CD4+ Tcells specific for both a myelin and a neuronal self-antigen in mice
Myelin oligodendrocyte glycoprotein induces incomplete tolerance of CD4+ Tcells specific for both a myelin and a neuronal self-antigen in mice
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DOI：
10.1002/eji.201646416
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发表时间：
2016-09-01
影响因子：
5.4
通讯作者：
Liblau, Roland S.
中科院分区：
文献类型：
--
作者：
Lucca, Liliana E.;Axisa, Pierre-Paul;Liblau, Roland S.
T细胞的多特异性，预测单个T细胞识别相关配体的连续体，意味着多个抗原可以耐受特定自身抗原的T细胞。我们先前在C57BL/6小鼠身上显示，部分针对髓鞘少突胶质细胞糖蛋白(MOG)35-55的CD4(+)T细胞谱系也识别神经元抗原神经丝介质(NF-M)15-35。这种双特异性的CD4(+)T细胞很常见，在刺激后会产生炎性细胞因子。由于识别两种自身抗原的T细胞预计会被更有效地耐受，这一发现促使我们研究多特异性如何影响耐受。我们发现，与MOG类似，核因子-M在胸腺中由胸腺髓质上皮细胞表达，胸腺上皮细胞是一种耐受性群体。然而，MOG(35-55)反应性CD4(+)T细胞的频率、表型和转移实验性自身免疫性脑脊髓炎(EAE)的能力在MOG缺陷小鼠中增加，但在NF-M缺陷小鼠中没有。我们发现I-A(B)在树突状细胞上呈递NF-M15-35的时间很短，这表明MHC II类结合不稳定。一贯地，将MHC锚定残基引入NF-M15-35(NF-M(15-35)T20Y)可提高其免疫原性，激活能够诱导EAE的谱系。我们的结果表明，在C57BL/6小鼠中，双特异性脑源性T细胞由于对两种自身抗原的低效暴露而设法逃脱耐受。
T-cell polyspecificity, predicting that individual Tcells recognize a continuum of related ligands, implies that multiple antigens can tolerize Tcells specific for a given self-antigen. We previously showed in C57BL/6 mice that part of the CD4(+) T-cell repertoire specific for myelin oligodendrocyte glycoprotein (MOG) 35-55 also recognizes the neuronal antigen neurofilament medium (NF-M) 15-35. Such bi-specific CD4(+) Tcells are frequent and produce inflammatory cytokines after stimulation. Since Tcells recognizing two self-antigens would be expected to be tolerized more efficiently, this finding prompted us to study how polyspecificity impacts tolerance. We found that similar to MOG, NF-M is expressed in the thymus by medullary thymic epithelial cells, a tolerogenic population. Nevertheless, the frequency, phenotype, and capacity to transfer experimental autoimmune encephalomyelitis (EAE) of MOG(35-55)-reactive CD4(+) Tcells were increased in MOG-deficient but not in NF-M-deficient mice. We found that presentation of NF-M15-35 by I-A(b) on dendritic cells is of short duration, suggesting unstable MHC class II binding. Consistently, introducing an MHC-anchoring residue into NF-M15-35 (NF-M(15-35)T20Y) increased its immunogenicity, activating a repertoire able to induce EAE. Our results show that in C57BL/6 mice bi-specific encephalitogenic Tcells manage to escape tolerization due to inefficient exposure to two self-antigens.