Interleukin (IL)-21 is a key regulator of T follicular helper (Tfh) cell development in germinal centers and represents a major cytokine secreted by Tfh cells that critically regulates the differentiation of memory B cells and plasma cells. IL-21 can also influence another small population of cells in the germinal center, known as T follicular regulatory (Tfr) cells, which negatively regulate Tfh-directed germinal center responses. These Tfr cells share some phenotypic markers (CXCR5+BCL6+ICOS+PD1+) with Tfh cells, but they also express the transcription factor FoxP3. This study showed that Tfr cells can interact directly with Tfh cells to suppress their production and secretion of IL-21 and IL-4, thereby decreasing B cell immunoglobulin production. Tfr cells can also interact directly with B cells in the germinal center, inhibiting several metabolic pathways and diminishing their effector function. IL-21 can overcome the effects of Tfr, both by inhibiting their proliferation and by upregulating glycolysis in B cells, making them resistant to suppression by Tfr. Although IL-4 plays an important role in germinal center B cell responses, unlike IL-21, it cannot overcome Tfr-mediated suppression. This Recommendation is of an article referenced in an F1000 Faculty Review also written by Rosanne Spolski, Daniel Gromer, and Warren J. Leonard.