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

G Chen, K Hardy, K Bunting, S Daley, L Ma… - The Journal of …, 2010 - journals.aai.org
G Chen, K Hardy, K Bunting, S Daley, L Ma, MF Shannon
The Journal of Immunology, 2010journals.aai.org
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 …
Abstract
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.
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