Block of both TGF-β and IL-2 signaling impedes Neurophilin-1+ regulatory T cell and follicular regulatory T cell development

Understanding the mechanisms that lead to autoimmunity is critical for defining potential therapeutic pathways. In this regard there have been considerable efforts in investigating the interacting roles of TGF-beta and IL-2 on the function regulatory T cells. We have taken advantage of dnTGF-beta RII II2ra(-/-)(abbreviated as II2ra(-/-)Tg) mouse model, which allows a direct mechanistic approach to define the relative roles of TGF-beta and IL-2 on Treg development. II2ra(-/-)Tg mice spontaneously developed multi-organ autoimmune diseases with expansion of pathogenic T cells and enhanced germinal center response at 3-4 weeks of age. Importantly, peripheral Treg cells from II2ra(-/-)Tg mice demonstrated an activated Th1-like stable phenotype and normal in vitro suppressive function, while thymus Treg increased but manifested decreased suppressive function. Interestingly, neither thymus nor peripheral Treg cells of II2ra(-/-)Tg mice contained Neuropilin-1(+) or PD-1(hi) phenotype, resulting in defective follicular regulatory T (Tfr) cell development. Such defective Tfr development led to elevated follicular T helper cells, enhanced germinal center responses and increased plasma cell infiltration. These data demonstrate an important synergetic role of TGF-beta and IL-2 in the generation, activation and stability of Treg cells, as well as their subsequent development into Tfr cells.