Leonard John D, Gilmore Dana C, Dileepan Thamotharampillai, Nawrocka Wioletta I, Chao Jaime L, Schoenbach Mary H, Jenkins Marc K, Adams Erin J, Savage Peter A
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Immunity. 2017 Jul 18;47(1):107-117.e8. doi: 10.1016/j.immuni.2017.06.015. Epub 2017 Jul 11.
Regulatory T (Treg) cells expressing the transcription factor Foxp3 are critical for the prevention of autoimmunity and the suppression of anti-tumor immunity. The major self-antigens recognized by Treg cells remain undefined, representing a substantial barrier to the understanding of immune regulation. Here, we have identified natural Treg cell ligands in mice. We found that two recurrent Treg cell clones, one prevalent in prostate tumors and the other associated with prostatic autoimmune lesions, recognized distinct non-overlapping MHC-class-II-restricted peptides derived from the same prostate-specific protein. Notably, this protein is frequently targeted by autoantibodies in experimental models of prostatic autoimmunity. On the basis of these findings, we propose a model in which Treg cell responses at peripheral sites converge on those self-proteins that are most susceptible to autoimmune attack, and we suggest that this link could be exploited as a generalizable strategy for identifying the Treg cell antigens relevant to human autoimmunity.
表达转录因子Foxp3的调节性T（Treg）细胞对于预防自身免疫和抑制抗肿瘤免疫至关重要。Treg细胞识别的主要自身抗原仍不明确，这是理解免疫调节的一个重大障碍。在此，我们在小鼠中鉴定出了天然Treg细胞配体。我们发现两个重复性Treg细胞克隆，一个在前列腺肿瘤中普遍存在，另一个与前列腺自身免疫性病变相关，它们识别来自同一前列腺特异性蛋白的不同且不重叠的MHC-II类限制性肽段。值得注意的是，在前列腺自身免疫的实验模型中，这种蛋白经常成为自身抗体的靶标。基于这些发现，我们提出了一个模型，其中外周部位的Treg细胞反应集中于那些最易受到自身免疫攻击的自身蛋白，并且我们认为这种联系可被用作一种通用策略来鉴定与人类自身免疫相关的Treg细胞抗原。
