Novel function of perforin in regulating CD4+ T cell activation by affecting calcium signaling (35.7)

Abstract

Abstract Perforin is a pore forming protein engaged mainly in mediating target-cell death and is employed by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. However, whether it also plays a role in conventional CD4+ T cell function remains unclear. Here we report that in perforin-deficient(PKO) mice, CD4+ T cells are hyperproliferative in response to TCR stimulation. This feature of activated CD4+ T cells is accompanied by an enhancement both in cell division and in IL-2 secretion. The perforin deficiency does not appear to influence T cell development in thymus and lymph node. In vivo, perforin deficiency results in increased antigen-specific T cell proliferation and antibody production. Furthermore, PKO mice appear more susceptible to experimental autoimmune uveitis. Examination of the mechanisms involved demonstrate that in PKO CD4+ T cells TCR stimulation increases intracellular calcium flux and subsequently enhances activation of transcription factor NF-AT1. Our results indicate that perforin plays a negative role in regulating CD4+ T cell activation and immune response by affecting TCR-dependent Ca2+ signaling.