FoxP3+RORγt+ T Helper Intermediates Display Suppressive Function against Autoimmune Diabetes

Recently, traces of double-positive FoxP3(+)RORgammat(+) T cells were identified and viewed as dual programming differentiation intermediates geared toward development into T regulatory or Th17 cells. In this study, we report that FoxP3(+)RORgammat(+) intermediates arise in the NOD mouse T cell repertoire prior to inflammation and can be expanded with tolerogen without further differentiation. Furthermore, FoxP3(+)RORgammat(+) cells express both CD62L and membrane-bound TGFbeta and use the former to traffic to the pancreas and the latter to suppress effector T cells both in vitro and in vivo. The cells perform these functions as FoxP3(+)RORgammat(+) intermediates, despite being able to terminally differentiate into either FoxP3(+)RORgammat(-) T regulatory or FoxP3(-)RORgammat(+) Th17 cells on polarization. These previously unrecognized observations extend plasticity to both differentiation and function and indicate that the intermediates are poised to traffic to sites of inflammation and target diverse pathogenic T cells, likely without prior conditioning by effector T cells, thus broadening efficacy against autoimmunity.