Human regulatory T cells rapidly suppress T cell receptor-induced Ca(2+), NF-κB, and NFAT signaling in conventional T cells.
Sci Signal
; 4(204): ra90, 2011 Dec 20.
Article
en En
| MEDLINE
| ID: mdl-22375050
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Activación de Linfocitos
/
Receptores de Antígenos de Linfocitos T
/
FN-kappa B
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Linfocitos T Reguladores
/
Señalización del Calcio
/
Factores de Transcripción NFATC
/
Tolerancia Inmunológica
Límite:
Humans
Idioma:
En
Revista:
Sci Signal
Asunto de la revista:
CIENCIA
/
FISIOLOGIA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Alemania
Pais de publicación:
Estados Unidos