IL-21 and T follicular helper cells.

Upon encounter with antigen, CD4(+) T cells differentiate into effector T(h) subsets with distinctive functions that are related to their unique cytokine profiles and anatomical locations. One of the most important T(h) functions is to provide signals to developing B cells that induce specific and appropriate antibody responses. The major CD4(+) T cell subset that helps B cells is the T follicular helper (T(FH)) cell, whose expression of the chemokine receptor CXCR5 [chemokine (C-X-C motif) receptor 5] serves to localize this cell to developing germinal centers (GCs) where it provides instructive signals leading to Ig class switching and somatic mutation. T(FH) cells produce high levels of IL-21, a cytokine that is critical for GC formation and also for the generation of T(FH) cells. Although T(FH) cells have been found to produce cytokines characteristic of other T(h) subsets, they represent a distinct lineage whose development is driven by the transcription factor B-cell CLL lymphoma-6 (BCL6). Consistent with their critical role in the generation of antibody responses, dysregulated T(FH) function has been associated with the development of systemic autoimmunity. Here, we review the role of IL-21 in the regulation of normal T(FH) development and function as well as in progression of autoimmune responses.