IL-21 and T follicular helper cells

Abstract

Upon encounter with antigen, CD4+ T cells differentiate into effector Th subsets with distinctive functions that are related to their unique cytokine profiles and anatomical locations. One of the most important Th 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 (TFH) 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. TFH cells produce high levels of IL-21, a cytokine that is critical for GC formation and also for the generation of TFH cells. Although TFH cells have been found to produce cytokines characteristic of other Th 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 TFH function has been associated with the development of systemic autoimmunity. Here, we review the role of IL-21 in the regulation of normal TFH development and function as well as in progression of autoimmune responses.