ORIGINAL ARTICLE

Cell Research (2009): 1-12
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Novel function of perforin in negatively regulating CD4⁺ T cell activation by affecting calcium signaling

Enguang Bi¹, Chunjian Huang¹, Yu Hu¹, Xiaodong Wu¹, Weiwen Deng¹, Guomei Lin¹, Zhiduo Liu¹, Lin Tian¹, Shuhui Sun², Kairui Mao¹, Jia Zou¹, Yuhan Zheng¹ and Bing Sun^1,3

Correspondence: Bing Sun, Tel: +86-21-63851927; Fax: +86-21-63843571 E-mail: bsun@sibs.ac.cn

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Perforin is a pore-forming protein engaged mainly in mediating target T cell death and is employed by cytotoxic T lymphocytes (CTLs) and natural killer 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 T cell receptor (TCR) stimulation. This feature of hyperproliferation is accompanied by the enhancement both in cell division and in IL-2 secretion. It seems that the perforin deficiency does not influence T cell development in thymus spleen and lymph node. In vivo, perforin deficiency results in increased antigen-specific T cell proliferation and antibody production. Furthermore, PKO mice are more susceptible to experimental autoimmune uveitis. To address the molecular mechanism, we found that after TCR stimulation, CD4⁺ T cells from PKO mice display an increased intracellular calcium flux and subsequently enhance activation of transcription factor NFAT1. Our results indicate that perforin plays a negative role in regulating CD4⁺ T cell activation and immune response by affecting TCR-dependent Ca²⁺ signaling.

Cell Research advance online publication 17 March 2009; doi: 10.1038/cr.2009.32

Keywords: perforin, T cell activation, TCR signal, autoimmune disease, Ca²⁺ signaling