Novel function of perforin in negatively regulating CD4(+) T cell activation by affecting calcium signaling.
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.
Bi
Enguang
E
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Huang
Chunjian
C
Hu
Yu
Y
Wu
Xiaodong
X
Deng
Weiwen
W
Lin
Guomei
G
Liu
Zhiduo
Z
Tian
Lin
L
Sun
Shuhui
S
Mao
Kairui
K
Zou
Jia
J
Zheng
Yuhan
Y
Sun
Bing
B
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*
D015704:CD4 Antigens; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D054353:Perforin