Ndfip proteins control Treg cell fate and function to prevent autoimmune disease.

Abstract

Abstract Regulatory T cells (Tregs) are key immune cells for enforcing peripheral tolerance against self. Supporting this, in humans and in mice, a defect in Treg number or function results in severe autoimmune disease. Tregs limit autoimmunity by restraining the activation and cytokine production of conventional T cells (among other mechanisms). Our data reveal how two E3 ubiquitin ligase-activating proteins, Ndfip1 and Ndfip2, regulate Treg fate and function. Ndfip (Nedd4 family interacting proteins) 1 and 2 are known to activate several members of the Nedd4-family of E3 ligases, such as Itch, that have known roles in T cells. We generated mice that constitutively lack Ndfip2 and conditionally lack Ndfip1 in Foxp3+ cells (Treg cDKO mice). These Treg cDKO mice, display severe spleen and lung pathology marked by pulmonary arterial fibrosis, and ectopic lymphoid follicles. Additionally, Treg cDKO mice have higher circulating antibody levels. Since Foxp3 is an X-linked gene, we expect female DKO Treg mice to have both normal and Ndfip-deficient Tregs. Surprisingly, we find that even these female mice are characterized by splenomegaly, pulmonary arterial fibrosis, and these mice show circulating autoantibodies by 16 weeks of age. We will present data explaining why both male and female Treg cDKO mice get sick and discuss the roles of Ndfip-proteins in Treg activation, Treg cytokine production, PD-1 expression, and FoxP3 stability.