A Broad Range of Self-Reactivity Drives Thymic Regulatory T Cell Selection to Limit Responses to Self

SummaryThe degree of T cell self-reactivity considered dangerous by the immune system, thereby requiring thymic selection processes to prevent autoimmunity, is unknown. Here, we analyzed a panel of T cell receptors (TCRs) with a broad range of reactivity to ovalbumin (OVA323-339) in the rat insulin promoter (RIP)-mOVA self-antigen model for their ability to trigger thymic self-tolerance mechanisms. Thymic regulatory T (Treg) cell generation in vivo was directly correlated with in vitro TCR reactivity to OVA-peptide in a broad ∼1,000-fold range. Interestingly, higher TCR affinity was associated with a larger Treg cell developmental “niche” size, even though the amount of antigen should remain constant. The TCR-reactivity threshold to elicit thymic negative selection and peripheral T cell responses was ∼100-fold higher than that of Treg cell differentiation. Thus, these data suggest that the broad range of self-reactivity that elicits thymic Treg cell generation is tuned to secure peripheral tolerance to self.

► Treg cell development is correlated with self-reactivity over a broad range
► Foreign antigen reactive Treg cells may be generated by cross-reactivity to self
► TCR affinity is correlated with the size of the Treg cell developmental “niche”
► Peripheral responses need greater self-reactivity than thymic Treg cell selection