T_Reg cells offer a bespoke service

Regulatory T (T_Reg) cells provide tailor-made control of the immune response, according to new research by Alexander Rudensky and colleagues. Effector CD4⁺ T cells differentiate into functionally distinct T helper (T_H) cell populations — T_H1, T_H2 and T_H17 cells — depending on the environmental milieu; these same conditions are now shown to induce the differentiation of a corresponding T_Reg cell population to specifically regulate these T_H cells.

The differentiation of T_H17 cells involves the activation of signal transducer and activator of transcription 3 (STAT3). The authors found that phosphorylated (activated) STAT3 also has a function in T_Reg cells by binding forkhead box P3 (FOXP3), which is a crucial transcription factor for T_Reg cell development. Mice with a conditional deletion of Stat3 in only their T_Reg cells (Foxp3^CreStat3^fl/fl mice) developed splenomegaly and enlargement of the mesenteric lymph nodes draining the gastrointestinal tract by 6 weeks of age, which progressed to inflammatory bowel disease by 12–14 weeks of age. In contrast to the systemic lymphoproliferative disorder of T_Reg cell-deficient mice, pathology in Foxp3^CreStat3^fl/fl mice was limited to the intestinal mucosa, which indicates that only a subset of T_Reg cell functions are affected by deficiency of STAT3.

The Foxp3^CreStat3^fl/fl mice had more CD4⁺ effector T cells producing the T_H17 cell cytokine interleukin-17 (IL-17) in the gut, whereas the production of T_H1 and T_H2 cell cytokines was similar in Foxp3^CreStat3^fl/fl and control mice. IL-17 production was shown to be the initial trigger for colitis induction in Foxp3^CreStat3^fl/fl mice. The co-transfer of STAT3-sufficient T_Reg cells completely abrogates the systemic, multi-organ autoimmunity that results from transfer of effector CD4⁺ T cells to immunodeficient mice. By contrast, the co-transfer of STAT3-deficient T_Reg cells with effector CD4⁺ T cells prevented systemic disease but resulted in an increased frequency of IL-17-producing CD4⁺ T cells in the gut and the development of colitis, which supports the selective dysregulation of T_H17 cell responses in Foxp3^CreStat3^fl/fl mice.

These results show that STAT3 expression by T_Reg cells is required for the control of T_H17 cell responses, and the authors suggest several possible mechanisms for this by comparing the expression patterns of FOXP3-dependent genes in STAT3-sufficient and -deficient T_Reg cells. First, STAT3 is required for the production of suppressor molecules such as IL-10 and IL-35 that are important for preventing colitis. Second, STAT3-dependent expression of the receptors for IL-1 and IL-6 could enable T_Reg cells to compete with T_H17 cells for essential activation cues. Third, the expression of CC-chemokine receptor 6 by T_Reg cells, as well as T_H17 cells, in a STAT3-dependent manner controls their migration to and therefore their spatial proximity in the gut. Finally, STAT3 activation in T_Reg cells inhibits the expression of soluble mediators of T_H17 cell differentiation, such as transforming growth factor-β and vasoactive intestinal peptide.

So, this study not only confirms that T_Reg cells can directly suppress T_H17 cell responses but also shows that transcription factors such as STAT3 can integrate environmental cues to provide 'class-specific' immune regulation.