IL-21 is a 17 kDa immunomodulatory cytokine produced mainly by NKT, T helper (Th) 17 and T follicular helper (TFH) cells. In TFH cells, IL-21 expression leads to autocrine signaling through the IL-21 receptor (IL-21R) and STAT3, which leads to additional transcriptional activation by Bcl-6. As with IFN gamma for Th1, IL-4 for Th2 cells, and IL-17A for Th17 cells, IL-21 is critical for TFH effector function. This cytokine plays a role in T cell-dependent B cell differentiation into plasma cells and memory cells, stimulation of IgG production and induction of apoptotic signaling in naïve B cells.

In Th17 cells, IL-21 expression and autocrine feedback through STAT3, IRF4 and ROR gamma t lead to upregulation of the IL-23R, thereby preparing Th17 cells for maturation and maintenance by the inflammatory cytokine IL-23. While upregulating IRF4 and ROR gamma t, IL-21 also mediates the downregulation of Foxp3. High levels of IL-21 are present in chemically-induced colitis models. IL-21-deficient mice are protected from developing colitis upon chemical treatment by their inability to upregulate Th17-associated molecules.

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ELISPOT