IL-15Ralpha is a negative regulator of TCR-activated proliferation in CD4+ T cells.
Although IL-15 is known to be a T cell growth factor, the function in T cells of IL-15Ralpha, its high affinity receptor, remains unclear. We found that murine IL-15Ralpha(-/-) CD4(+) T cells hyperproliferated in response to TCR stimulation, in vitro and in vivo, and displayed a lower TCR activation threshold than wild-type CD4(+) T cells. TCR-induced activation of Zap70 and of the phospholipase C-gamma1-NFATp, Ras-ERK-c-Fos, and Rac-JNK-c-Jun pathways was all augmented in IL-15Ralpha(-/-) CD4(+) T cells. This in turn led to earlier IL-2Ralpha induction and higher IL-2 production, which most likely contribute to the hyperproliferation of IL-15Ralpha(-/-) CD4(+) T cells. Exogenous IL-15 reduced levels of TCR-activated signals, transcription factors, IL-2, and IL-2Ralpha, and division in wild-type CD4(+) T cells. These results reveal IL-15Ralpha to be a negative regulator for CD4(+) T cell activation and demonstrate a novel layer of regulation of TCR signaling by a cytokine system.
Lee
Jan-Mou
JM
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Chung
Chen-Yen
CY
Chiang
Wei-Wei
WW
Liou
Yae-Huei
YH
Chen
Chian-Feng
CF
Liao
Nan-Shih
NS
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
C508025:Il15ra protein, mouse; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2