TCF-1 negatively regulates the suppressive ability of canonical and non-canonical Tregs.

Regulatory T cells (Tregs) are suppressive immune cells used in various clinical and therapeutic applications. Canonical Tregs (canTregs) express CD4, FOXP3, and CD25, which are considered definitive markers of their Treg status when expressed together. However, a subset of noncanonical Tregs (ncTregs) expressing only CD4 and FOXP3 have recently been described in some infection contexts. Using a unique mouse model for the first time demonstrated that the TCF-1 regulation of Tregs suppressive function is not limited to the thymus during development. Our data showed that TCF-1 also regulated Tregs suppressive ability in secondary organs and GVHD target organs as well as upregulating ncTregs. Our data demonstrated that TCF-1 regulates the suppressive function of Tregs through critical molecules like GITR and PD-1, specifically by means of ncTregs. Our in vitro approaches shows that TCF-1 regulates the Treg effector-phenotype and the molecules critical for Treg migration to the site of inflammation. Using in vivo models, we show that both canTreg and ncTregs from TCF-1 cKO mice have a superior suppressive function, as shown by their ability to control conventional T cell proliferation, avert acute graft-versus-host disease (GVHD) and limit tissue damage. Thus, for the first time, we provide evidence that TCF-1 negatively regulates the suppressive ability of canTreg and ncTregs. These findings provide evidence that TCF-1 is a novel target for developing strategies to treat alloimmune disorders.