FoxP3(+)ROR gamma t(+) T Helper Intermediates Display Suppressive Function against Autoimmune Diabetes

Recently, traces of double-positive FoxP3(+)ROR gamma t(+) 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(+)ROR gamma t(+) intermediates arise in the NOD mouse T cell repertoire prior to inflammation and can be expanded with tolerogen without further differentiation. Furthermore, FoxP3(+)ROR gamma t(+) cells express both CD62L and membrane-bound TGF beta 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(+)ROR gamma t(+) intermediates, despite being able to terminally differentiate into either FoxP3(+)ROR gamma t(-) T regulatory or FoxP3(-)ROR gamma t(+) 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. The Journal of Immunology, 2010, 184: 3377-3385.