IL-15Rα 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-15Rα, its high affinity receptor, remains unclear. We found that murine IL-15Rα^-/- 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-γ1-NFATp, Ras-ERK-c-Fos, and Rac-JNK-c-Jun pathways was all augmented in IL-15Rα^-/- CD4⁺ T cells. This in turn led to earlier IL-2Rα induction and higher IL-2 production, which most likely contribute to the hyperproliferation of IL-15Rα^-/- CD4 ⁺ T cells. Exogenous IL-15 reduced levels of TCR-activated signals, transcription factors, IL-2, and IL-2Rα, and division in wild-type CD4⁺ T cells. These results reveal IL-15Rα to be a negative regulator for CD4⁺ T cell activation and demonstrate a novel layer of regulation of TCR signaling by a cytokine system.