Human Regulatory T Cells Rapidly Suppress T Cell Receptor–Induced Ca 2+ , NF-κB, and NFAT Signaling in Conventional T Cells

Inhibition of calcium signaling is critical for the suppression of T cell responses by regulatory T cells. Regulatory T cells (T regs ) are required to keep conventional T cells in check, and disruption of the generation or function of T regs leads to autoimmunity. Conversely, T regs can have a deleterious effect by dampening antitumor responses of T cells. Thus, improved understanding of the mechanisms by which T regs inhibit T cell receptor (TCR)–induced responses in conventional T cells would help to develop better therapies against autoimmune disorders and cancer. Schmidt et al . found that TCR-induced, Ca 2+ -dependent signaling in human conventional T cells that were incubated with T regs was inhibited compared to that in nonsuppressed T cells, which led to defective activation of the transcription factors NFAT and NF-κB. In contrast, Ca 2+ -independent signaling was unaffected. Suppressed signaling persisted after the T regs were removed from cocultures. Increasing the intracellular concentration of Ca 2+ in conventional T cells reversed the inhibitory effects of T regs . Together, these data suggest that inhibition of Ca 2+ signaling is critical for the suppressive effects of T regs . 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