c‐Rel but not NF‐κB1 is important for T regulatory cell development

Abstract

Regulatory T (Treg) cells are crucial for maintaining peripheral tolerance and controlling T-cell responses. The generation of Treg in the thymus requires TCR triggering and CD28 costimulation. Engagement of these receptors induces a number of signalling pathways, including the activation of NF-jB via PKCh and the Bcl-10/CARMA1/MALT complex. Previous studies have shown that PKCh, Bcl-10 and CARMA1 are important for Treg development. It is unclear, however, whether different members of the NF-jB family contribute to Treg development or homeostasis. In this study, we show that Treg numbers are reduced in the absence of c-Rel but not NF-jB1 (p50). Furthermore, using mixed bone marrow chimeras from WT and KO animals, we demonstrate that the requirement for PKCh, Bcl-10 and c-Rel is T-cell intrinsic, and cannot be rescued by the presence of WT cells. Therefore, c-Rel and NF-jB1 have differential roles in Treg development.

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

“…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]. The reduced Treg numbers in c-Rel-deficient mice results from a Treg-intrinsic defect rather than from the defective IL-2 production by conventional T cells, because the presence of wild-type cells failed to rescue the impaired Treg development from c-Rel-deficient bone marrow cells in mixed bone marrow chimeras [17,19,21,22]. Moreover, Long et al [20] showed that NF-kB proteins are the mediator that translates TCR signals into Foxp3 transcription in thymocytes, because enhanced NF-kB activity (by transgenic expression of a constitutive active inhibitor of IkB kinase 2) was sufficient for Foxp3 induction in CD4SP thymocytes (and surprisingly in CD8SP thymocytes as well), expressing a monoclonal transgenic TCR that otherwise does not support Foxp3 1 Treg differentiation.…”

“…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].…”

“…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]. The reduced Treg numbers in c-Rel-deficient mice results from a Treg-intrinsic defect rather than from the defective IL-2 production by conventional T cells, because the presence of wild-type cells failed to rescue the impaired Treg development from c-Rel-deficient bone marrow cells in mixed bone marrow chimeras [17,19,21,22].…”

“…Foxp3 1 T cells generated in transgenic mice with enhanced NF-kB signaling showed demethylation of the TSDR [20], suggesting that c-Rel may be at least sufficient for the chromatin remodeling of the Foxp3 locus; however, these transgenic Foxp3 1 T cells were predominantly CD25 À and lacked full suppressor function [20]. In addition, c-Rel-deficient Treg, despite the reduction in numbers, are fully suppressive [17,19] and show a gene expression profile similar to wild-type Treg [19]. Thus, c-Rel may be neither absolutely necessary nor sufficient to specify many features of the Treg phenotype.…”