title: Novel function of perforin in negatively regulating CD4(+) T cell activation by affecting calcium signaling.
abstract: 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.
authors.affiliation: Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Enguang
authors.initials: E
authors.lastname: Bi
authors.forename: Chunjian
authors.initials: C
authors.lastname: Huang
authors.forename: Yu
authors.initials: Y
authors.lastname: Hu
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wu
authors.forename: Weiwen
authors.initials: W
authors.lastname: Deng
authors.forename: Guomei
authors.initials: G
authors.lastname: Lin
authors.forename: Zhiduo
authors.initials: Z
authors.lastname: Liu
authors.forename: Lin
authors.initials: L
authors.lastname: Tian
authors.forename: Shuhui
authors.initials: S
authors.lastname: Sun
authors.forename: Kairui
authors.initials: K
authors.lastname: Mao
authors.forename: Jia
authors.initials: J
authors.lastname: Zou
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Zheng
authors.forename: Bing
authors.initials: B
authors.lastname: Sun
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D020013:Calcium Signaling; D002455:Cell Division; D005260:Female; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism; D054353:Perforin / Q000172:deficiency / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D054353:Perforin