Factors influencing regulatory T cell maintenance for the control of autoimmunity

Regulatory T cells (Tregs) are a subset of CD4+ T cells with suppressive function and are critical in limiting autoimmunity. Increasing Treg numbers can be beneficial in the treatment of several inflammatory disorders. Here, we investigate the roles played by various factors on the control of Treg homeostasis. We provide evidence that the skin can exert strong systemic effects on Treg numbers by producing the cytokine thymic stromal lymphopoietin (TSLP) in response to topical administration of the vitamin D3 analog MC903. Widespread increases in Tregs were observed in mice treated topically but not systemically with MC903. TSLP receptor (TSLP-R) but not hematopoietic vitamin D receptor signaling was important for this increase in Treg numbers and MC903 treatment did not lead to changes in Treg development, but drove increased Treg proliferation. However, TSLP-R expression by Tregs themselves was not required for the expansion induced by MC903 treatment. Rather, TSLP promotes Treg proliferation by affecting dendritic cell (DC)/Treg interactions, as mice lacking DCs did not have an increase in Tregs after MC903 treatment, and TSLP enhanced proliferation of Tregs co-cultured with DCs. To test whether MC903 could influence progression of autoimmunity, non-obese diabetic (NOD) mice were treated topically with MC903 and it was found that this treatment significantly lowered the incidence of diabetes. Other than TSLP-driven expansion, Treg numbers are known to rely on the cytokine interleukin-2 (IL-2) and T cell receptor (TCR) signals. We found that Foxp3- conventional T cells (Tconvs) produce IL-2 in response to self-peptides and that Tconvs possessing TCRs with greater self-reactivity express more IL-2 at baseline. Furthermore, selective disruption of TCR signaling in Tconvs led to a trend towards decreased expression of IL-2 and diminished the ability of Tconvs to maintain Treg numbers. These data suggest that the role of TCR in Treg maintenance includes the ability of Tconvs to signal in response to self-peptides. Together, this work investigates multiple factors that have important effects on Treg maintenance. These findings have potential implications on development of therapies that seek to modulate immune activation in autoimmune settings