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 (T_eff) and T regulatory (T_reg) CD4⁺Foxp3⁺ cells. In vivo T_eff are present in all immune organs whereas the TPO-specific T_reg 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 T_eff and the depletion of T_reg 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.