E Badami et al. "Activation-induced cell death of self-reactive regulatory T cells drives autoimmunity"

Activation of self-reactive T cells is a major driver to autoimmunity and is suppressed by mechanisms of regulation. In a humanized model of autoimmune thyroiditis, we investigated the mechanism underlying break of tolerance. Here we found that a human TCR specific for the self-antigen thyroid peroxidase (TPO) is positively selected in the thymus of RAG KO mice on both T effector (Teff) and T regulatory (Treg) CD4+Foxp3+ cells.. In vivo Teff are present in all immune organs whereas the TPO-specific Treg are present in all lymphoid organs with the exception of the thyroid draining lymph nodes. We suggest that the presence of TPO in the thyroid draining lymph nodes induces the activation of Teff and the depletion of Treg via activation induced cells death (AICD). Our findings provide new insights on the failure of the mechanisms of immune tolerance, with potential implications in designing immunotherapeutic strategies.自身反应性T细胞的活化是自身免疫疾病的核心驱动因素，且可通过免疫调控机制予以抑制。在自身免疫性甲状腺炎的人源化模型中，本研究探究了免疫耐受破缺的潜在机制。研究发现，靶向自身抗原甲状腺过氧化物酶（thyroid peroxidase, TPO）的人源T细胞受体（TCR），可在RAG敲除小鼠（RAG KO mice）的胸腺中，对效应T细胞（Teff）与调节性T细胞（Treg，即CD4+Foxp3+细胞）两类群体完成阳性选择。体内的效应T细胞分布于所有免疫器官，而靶向TPO的调节性T细胞则仅存在于除甲状腺引流淋巴结外的所有淋巴器官中。我们推测，甲状腺引流淋巴结中存在的TPO可通过活化诱导的细胞死亡（activation induced cell death, AICD）途径，诱导效应T细胞活化并耗竭调节性T细胞。本研究结果为免疫耐受机制的失衡提供了全新见解，同时为免疫治疗策略的开发提供了潜在参考方向。