T-cell help in the germinal center: homing in on the role of IL-21

Interleukin 21 (IL-21) is a pleiotropic cytokine that is overproduced in multiple autoimmune settings. Provision of IL-21 from follicular helper T cells is an important component of T-cell help within germinal centers (GC), and the last few years have seen a resurgence of interest in IL-21 biology in the context of the GC environment. While it has been more than a decade since T cell-derived IL-21 was found to upregulate B-cell expression of the GC master transcription factor B-cell lymphoma 6 (Bcl-6) and to promote GC expansion, several recent studies have collectively delivered significant new insights into how this cytokine shapes GC B-cell selection, proliferation, and fate choice. It is now clear that IL-21 plays an important role in GC zonal polarization by contributing to light zone GC B-cell positive selection for dark zone entry as well as by promoting cyclin D3-dependent dark zone inertial cycling. While it has been established that IL-21 can contribute to the modulation of GC output by aiding the generation of antibody-secreting cells (ASC), recent studies have now revealed how IL-21 signal strength shapes the fate choice between GC cycle re-entry and ASC differentiation in vivo. Both provision of IL-21 and sensitivity to this cytokine are finely tuned within the GC environment, and dysregulation of this pathway in autoimmune settings could alter the threshold for germinal center B-cell selection and differentiation, potentially promoting autoreactive B-cell responses.