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IL-15R Is a Negative Regulator of TCR-Activated Proliferation in CD4⁺ T Cells¹

Jan-Mou Lee^*,, Chen-Yen Chung, Wei-Wei Chiang, Yae-Huei Liou, Chian-Feng Chen^*, and Nan-Shih Liao^2,*,

^* Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; and Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan

Although IL-15 is known to be a T cell growth factor, the function in T cells of IL-15R, its high affinity receptor, remains unclear. We found that murine IL-15R^–/– 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-1-NFATp, Ras-ERK-c-Fos, and Rac-JNK-c-Jun pathways was all augmented in IL-15R^–/– CD4⁺ T cells. This in turn led to earlier IL-2R induction and higher IL-2 production, which most likely contribute to the hyperproliferation of IL-15R^–/– CD4⁺ T cells. Exogenous IL-15 reduced levels of TCR-activated signals, transcription factors, IL-2, and IL-2R, and division in wild-type CD4⁺ T cells. These results reveal IL-15R to be a negative regulator for CD4⁺ T cell activation and demonstrate a novel layer of regulation of TCR signaling by a cytokine system.

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