Novel function of perforin in negatively regulating CD4^＋ T cell activation by affecting calcium signaling  

作　　者：Enguang Bi Chunjian Huang Yu Hu Xiaodong Wu Weiwen Deng Guomei Lin Zhiduo Liu Lin Tian Shuhui Sun Kairui Mao Jia Zou Yuhan Zheng Bing Sun 

机构地区：[1]Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China [2]Fudan University School of Medicine, Shanghai 200032, China [3]Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025, China

出　　处：《Cell Research》2009年第7期816-827,共12页细胞研究（英文版）

基　　金：Acknowledgments We thank Drs Hua Gu （Columbia University, USA）, Weiguo Zhang （Duke University Medical Center, USA）, and Youhai H Chen （University of Pennsylvania, USA） for reviewing the manuscript and for suggestions, and Dr Ilia Voskoboinik （Peter MacCallum Cancer Centre, Australia） for providing the mouse perforin cDNA in pKS（＋） Bluescript. Ragl^-/- mice were gifts from Xiaolong Liu （Shanghai Institutes for Biological Sciences, China）. This work was supported by grants from the National Natural Science Foundation of China （30325018, 30530700, 30623003, and 30421005） and CAS project （KSCX1-YW-R-43）, grants from the National Key Project 973 （2006CB504300 and 2007CB512404）, grants from the Technology Commission of Shanghai Municipality （04DZ14902, 04DZ19108, 06DZ22032, 04DZ19112, 07XD14033, and 07DZ22916）, 863 key project （2006AA02A247）, and a grant from the E-institutes of Shanghai Universities Immunology Division.

摘　　要：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 Ca^2＋ signaling.

关 键 词：PERFORIN T cell activation TCR signal autoimmune disease Ca^2＋ signaling 

分 类 号：Q25[生物学—细胞生物学] X51[环境科学与工程—环境工程]