THEMIS enhances the magnitude of normal and neuroinflammatory type 1 immune responses by promoting TCR-independent signals.

Signals that determine the differentiation of naïve CD4 + T helper (T H ) cells into specific effector cell subsets are primarily stimulated by cytokines, but additional signals are required to adjust the magnitude of T H cell responses and set the balance between effective immunity and immunological tolerance. By inducing the post-thymic deletion of the T cell lineage signaling protein THEMIS, we showed that THEMIS promoted the development of optimal type 1 immune responses to foreign antigens but stimulated signals that favored encephalitogenic responses to self-neuroantigens. THEMIS was required to stimulate the expression of the gene encoding the transcriptional regulator T-BET and the production of the cytokine interferon-γ (IFN-γ), and it enhanced the ability of encephalitogenic CD4 + T cells to migrate into the central nervous system. Consistently, analysis of THEMIS expression in polarized CD4 + T cells showed that THEMIS was selectively increased in abundance in T H 1 cells. The stimulation of predifferentiated effector CD4 + T cells with antigen-presenting cells revealed a stimulatory function for THEMIS on type 1 cytokine responses, similar to those observed ex vivo after immunization. In contrast, THEMIS exerted opposing effects on naïve CD4 + T cells in vitro by inhibiting the T cell receptor (TCR)-mediated signals that lead to T H 1 cell responses. These data suggest that THEMIS exerts TCR-independent functions in effector T cells, which increase the magnitude of normal and pathogenic T H 1 cell-mediated responses.