IL-21 and T follicular helper cells

Abstract

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.

Fig. 1.

The GC reaction is facilitated by the interaction between surface molecules on T_FH cells and developing B cells, both of which use CXCR5 to localize there. Interactions include the binding of ICOSL to ICOS, which leads to the up-regulation of c-Maf and subsequent production of high levels of IL-21 by T_FH cells. IL-21 then acts on T_FH in an autocrine manner to promote its function in GC B-cell development and antibody production. T_FH-cell-derived IL-21 can also bind to the IL-21R on B cells.

Fig. 2.

T_FH cells are developmentally related to other CD4⁺ T cell subsets. Although initially characterized as producing IL-21 but not cytokines associated with the T_h1, T_h2 and T_h17 subsets, evidence now indicates that T_FH cells localizing to the follicle through their expression of CXCR5 can also express IFNγ, IL-4 and IL-17. Treg cells are capable of undergoing conversion to T_FH cells in Peyer's patches. The green bars designate CXCR5.