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.