Mechanisms of T helper cell suppression by regulatory T cells

Abstract

Suppression by regulatory T cells (Tregs) is a mechanism of peripheral tolerance that controls self-reactive T cells by suppressing cytokine expression and effector functions of T helper (Th) and cytotoxic T cells. Intense research has focused on the characterization of the function and therapeutic uses of Tregs; however the mechanisms responsible for the inactivation of T cells by Tregs remain poorly characterized.;Previous results have shown that in response to tolerizing stimuli, members of the Nuclear Factor of Activated T cell (NFAT) family of transcription factors direct the expression of a specific set of genes, which encode proteins that are responsible for the inhibition of Th cell effector functions. Here, we show that NFAT proteins also play a crucial role in the mechanism that regulates nTreg-mediated suppression of effector Th cells. Our data show that when stimulated in the presence of nTregs, suppressed Th cells are still capable of translocating NFAT proteins into the nucleus, which leads to the upregulation of two NFAT1-dependent genes, Grail and Ikaros. Furthermore, Th cells from Nfat1-/- mice are resistant to nTreg-mediated suppression, but when NFAT1 expression is restored in these cells, their ability to be suppressed by Tregs is recovered. Our results also indicate that the expression of CTLA-4 in nTregs is required for the induction of the NFAT1-mediated expression of those "suppressor" genes in Th cells. Finally, we show evidence that this mechanism is specifically activated by FoxP3+ nTregs generated in the thymus but not by other population of T cells with regulatory function.;Our results demonstrate that NFAT1 is needed to induce a suppressed state in Th cells. These experiments duly correlate NFAT1 activation in suppressed Th cells with the expression of T cell inactivating genes, namely Grail and Ikaros. Both of these genes have previously been characterized as T cell inactivating genes, thereby providing a basis for how Th cells are maintained in a suppressed state. Our results indicate, thus, that NFAT1 activates a key mechanism responsible for nTreg-mediated suppression of Th cells.