IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses

Abstract

During T cell–dependent responses, B cells can either differentiate extrafollicularly into short-lived plasma cells or enter follicles to form germinal centers (GCs). Interactions with T follicular helper (Tfh) cells are required for GC formation and for selection of somatically mutated GC B cells. Interleukin (IL)-21 has been reported to play a role in Tfh cell formation and in B cell growth, survival, and isotype switching. To date, it is unclear whether the effect of IL-21 on GC formation is predominantly a consequence of this cytokine acting directly on the Tfh cells or if IL-21 directly influences GC B cells. We show that IL-21 acts in a B cell–intrinsic fashion to control GC B cell formation. Mixed bone marrow chimeras identified a significant B cell–autonomous effect of IL-21 receptor (R) signaling throughout all stages of the GC response. IL-21 deficiency profoundly impaired affinity maturation and reduced the proportion of IgG1+ GC B cells but did not affect formation of early memory B cells. IL-21R was required on GC B cells for maximal expression of Bcl-6. In contrast to the requirement for IL-21 in the follicular response to sheep red blood cells, a purely extrafollicular antibody response to Salmonella dominated by IgG2a was intact in the absence of IL-21.

IFN-γ–Producing CD4+ T Cells Promote Generation of Protective Germinal Center–Derived IgM+ B Cell Memory against Salmonella Typhi

“…The absence of IL-21 in the supernatants of CD4 + splenocytes with porin peptide-pulsed DCs and the lack of significantly altered anti-porin Ab responses in Il21r-deficient animals suggest that this cytokine does not play a role in the IgM GC B cell response. This finding is in line with a previous study showing that IL-21 is not required for the protective Ab response against Salmonella infection (58). However, IL-21 may provide critical support for IgM to IgG Ig switch during infection with other Gram-negative bacteria such as Ehrlichia muris (59), suggesting that these bacteria imprint a different cytokine pattern during infection.…”

IL-12 induced the generation of IL-21- and IFN-γ-co-expressing poly-functional CD4+ T cells from human naive CD4+ T cells

“…29 It has been reported that IL-21 improves the differentiation of Tfh cells by inducing Bcl6 and Cxcr5 mRNA in vitro. [30][31][32] Recently, Th1-like Tfh cells were proposed in many studies, which could express Th1 effector cytokine IFN-g and Tfh effector cytokine IL-21 in the same time. 20,21 In our previous studies, we found that the percentage of IL-21 C IFN-g C CD4 C cells was significantly higher in nasal polyp (NP) tissues compared with control tissues and matched PBMCs.…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…GCs are comprised of B cells and Tfh cells (which migrate into GCs following initial interaction with B cells at the margin of the B‐cell follicle), together with antigen‐bearing follicular dendritic cells (FDCs), macrophages, and stromal cells. B cells undergo further cognate interactions with Tfh cells in the light zones of the GC, in which help is again mediated via two‐way receptor‐ligand interactions and production of cytokines including IL‐21 102, 103, 104. This enables Tfh cells to control the affinity of B cells entering the GC reaction 105.…”