TCR signaling by conventional CD4(+) T cells is required for optimal maintenance of peripheral regulatory T cell numbers

To maintain immune tolerance, regulatory T cell (Treg) numbers must be closely indexed to the number of conventional T cells (Tconvs) so that an adequate Treg:Tconv ratio can be maintained. Two factors important in this process are the cytokine interleukin‐2 (IL‐2) and T cell receptor (TCR) stimulation by major histocompatibility complex class II (MHC‐II). Here, we report that in addition to TCR stimulation of Tregs themselves, the maintenance of Tregs also requires TCR signaling by Tconvs. We found that Tconvs produce IL‐2 in response to self‐peptide‐MHC‐II complexes and that Tconvs possessing more highly self‐reactive TCRs express more IL‐2 at baseline. Furthermore, selective disruption of TCR signaling in Tconvs led to a trend toward decreased expression of IL‐2 and attenuated their ability to maintain Treg numbers. These data suggest that in order to maintain an adequate Treg:Tconv ratio, Tregs are continuously indexed to self‐peptide‐MHC‐II‐induced TCR signaling of Tconvs. These results have implications in attempts to modulate immune tolerance, as Treg numbers adjust to the self‐reactivity, and ultimately IL‐2 production by the T cells around them.