Human Regulatory T Cells Rapidly Suppress T Cell Receptor-Induced Ca2+, 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 Tr-egs rapidly suppressed the release of calcium ions (Ca2+) from intracellular stores in response to T cell receptor (TCR) activation in T-cons. The inhibition of Ca2+ 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 kappa B (NF-kappa B). In contrast, Ca2+-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 Ca2+ 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-kappa B and of the expression of the gene encoding the cytokine interleukin-2 was reversed in T-cons by increasing the concentration of intracellular Ca2+. 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.