Human regulatory T cells rapidly suppress T cell receptor-induced Ca(2+), NF-κB, and NFAT signaling in conventional T cells.

CD4 + CD25 hi Foxp3 + regulatory T cells (T regs ) are critical mediators of self-tolerance, which is crucial for the prevention of autoimmune disease, but T regs can also inhibit antitumor immunity. T regs inhibit the proliferation of CD4 + CD25 − conventional T cells (T cons ), as well as the ability of these cells to produce effector cytokines; however, the molecular mechanism of suppression remains unclear. Here, we showed that human T regs rapidly suppressed the release of calcium ions (Ca 2+ ) from intracellular stores in response to T cell receptor (TCR) activation in T cons . The inhibition of Ca 2+ signaling resulted in decreased dephosphorylation, and thus decreased activation, of the transcription factor nuclear factor of activated T cells 1 (NFAT1) and reduced the activation of nuclear factor κB (NF-κB). In contrast, Ca 2+ -independent events in T cons , such as TCR-proximal signaling and activation of the transcription factor activator protein 1 (AP-1), were not affected during coculture with T regs . Despite suppressing intracellular Ca 2+ mobilization, coculture with T regs did not block the generation of inositol 1,4,5-trisphosphate in TCR-stimulated T cons . The T reg -induced suppression of the activity of NFAT and NF-κB and of the expression of the gene encoding the cytokine interleukin-2 was reversed in T cons by increasing the concentration of intracellular Ca 2+ . Our results elucidate a previously unrecognized and rapid mechanism of T reg -mediated suppression. This increased understanding of T reg function may be exploited to generate possible therapies for the treatment of autoimmune diseases and cancer.