Regulation of the IL-21 gene by the NF-κB transcription factor c-Rel

IL-21 is a member of the common γ-chain-dependent cytokine family and is a key modulator of lymphocyte development, proliferation, and differentiation. IL-21 is highly expressed in activated CD4⁺ T cells and plays a critical role in the expansion and differentiation of the Th cell subsets, Th17 and follicular helper T (T_FH) cells. Because of its potent activity in both myeloid and lymphoid cell immune responses, it has been implicated in a number of autoimmune diseases and has also been used as a therapeutic agent in the treatment of some cancers. In this study, we demonstrate that c-Rel, a member of the NF-κB family of transcription factors, is required for IL-21 gene expression in T lymphocytes. IL-21 mRNA and protein levels are reduced in the CD4⁺ cells of rel^-/- mice when compared with rel^+/+ mice in both in vitro and in vivo models. A c-Rel binding site identified in the proximal promoter of il21 is confirmed to bind c-Rel in vitro and in vivo and to regulate expression from the il21 promoter in T cells. Downstream of IL-21 expression, Th17, T_FH, and germinal center B cell development are also impaired in rel^-/- mice. The administration of IL-21 protein rescued the development of T ^FH cells but not germinal center B cells. Taken together, c-Rel plays an important role in the expression of IL-21 in T cells and subsequently in IL-21-dependent T^FH cell development.