Tim-1 expressed on dendritic cells enhances effector T cell responses and inhibits development and function of regulatory T cells (99.9)

Abstract

Abstract Tim-1 has been reported to be expressed on CD4+ T cells upon activation and to regulate Th2 responses. Here we report that Tim-1 is constitutively expressed on dendritic cells (DCs), the key instigators of adaptive immune responses. Tim-1 engagement in DCs induces a signaling cascade with NF-kB acivation, and promotes their maturation, resulting in upregulation of costimulatory molecules and production of proinflammatory cytokines. Such DCs enhance effector T cell (especially Th17) responses but inhibit de novo generation of Foxp3+ regulatory T cells (Treg). In vivo when given at the induction of immune response, agonistic anti-Tim-1 antibody enhances immunogenic function of DCs, decreases suppressive function of Foxp3+ Treg, and substantially increases proinflammatory Th17 responses as well as Th1 responses. The anti-Tim-1 treatment induces more severe experimental autoimmune encephalomyelitis (EAE) in susceptible mice, and also breaks tolerance and induces disease in the EAE-resistant strain of mice. These findings indicate that Tim-1 has an important role in the innate immune system in that Tim-1 signaling in DCs decreases immune regulation by Treg and promotes effector T cell responses.