c‐Rel is crucial for the induction of Foxp3⁺ regulatory CD4⁺ T cells but not T_H17 cells

Abstract

The NF-jB/Rel family member c-Rel was described to be required for the development of T H 1 responses. However, the role of c-Rel in the differentiation of T H 17 and regulatory CD41

c‐Rel: A pioneer in directing regulatory T‐cell lineage commitment?

“…Isomura et al [19] found that c-Rel-deficient naïve CD4 1 T cells normally upregulated Foxp3 when stimulated in the presence of TGF-b. Although Visekruna et al [18] found that TGF-b-mediated Foxp3 induction in c-Rel-deficient peripheral CD4 1 T cells is severely hampered, this defect was not cell autonomous but rather due to their defective IL-2 production, because addition of exogenous IL-2 did rescue the impaired Foxp3 induction. In contrast, Ruan et al [21] show that iTreg differentiation from c-Reldeficient CD4 1 CD25 À T cells was impaired to some degree even in the presence of exogenous IL-2.…”

“…It has remained unclear, however, which NF-kB family members are required, whether NF-kB proteins directly and/or indirectly regulate the Foxp3 gene, and how they do so. Two reports in this issue of the European Journal of Immunology by Deenick et al [17] and Visekruna et al [18], together with four recent reports published elsewhere [19][20][21][22], have now addressed these issues and suggest that it is c-Rel that pioneers Foxp3 induction and hence Treg differentiation in the thymus.…”

“…Deenick et al [17], Visekruna et al [18] and others have now analyzed mice lacking each member of the NF-kB proteins known to mediate TCR/CD28 signals and observed that c-Rel-deficient mice have reduced numbers of Foxp3 1 CD4SP cells in the thymus and in the periphery [17][18][19]21]. In contrast, NF-kB1-deficient mice had relatively normal numbers of these cells [17,19,21], while radiation chimeras reconstituted with RelA/p65-deficient bone marrow cells displayed modest reduction in CD25 1 Foxp3 1 CD4SP thymocyte numbers [19].…”

“…In their report, Visekruna et al [18] additionally addressed whether c-Rel is required for Th17 generation. They also found that c-Rel-deficient naïve CD4 1 T cells are fully capable of differentiating into Th17 cells when stimulated in vitro in the presence of TGF-b and IL-6, irrespectively of exogenous IL-2, although it remains to be addressed whether this is also the case in vivo.…”

“…They also found that c-Rel-deficient naïve CD4 1 T cells are fully capable of differentiating into Th17 cells when stimulated in vitro in the presence of TGF-b and IL-6, irrespectively of exogenous IL-2, although it remains to be addressed whether this is also the case in vivo. To determine a contribution of c-Rel to iTreg and Th17 generation in vivo, it would be important to examine the development of Foxp3 1 T cells and Th17 cells in the intestine of c-Rel-deficient mice, as the intestine is considered to be a site in which both iTreg and Th17 cells are generated efficiently to maintain immune homeostasis [25].…”