Abstract
Significance
In the present study, we provide evidence of a cellular mechanism of breach of tolerance in an in vivo model of spontaneous autoimmune thyroiditis (AIT). We observe that self-antigen (Ag) specific T
reg
circulate in all lymphatic tissues except for the lymph nodes (LNs) draining the thyroid, which represents the site of inflammation. By contrast, cognate effector T cells accumulate in the draining LNs and thyroid. The absence of T
reg
unleashes cognate T
eff
, which promote tissue destruction. We demonstrate that the organ-restricted disappearance of T
reg
is driven by the self-Ag, aberrantly expressed in a highly inflammatory environment, by a mechanism of activation-induced cell death.
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 cell death (AICD). Our findings provide insights on the failure of the mechanisms of immune tolerance, with potential implications in designing immunotherapeutic strategies.