IL-21 regulates germinal center B cell differentiation and proliferation through a B cell–intrinsic mechanism

By D. Zotos, J. Coquet, Yang Zhang, A. Light, K. D'Costa, A. Kallies, L. Corcoran, D. Godfrey, K. Toellner, M. Smyth and 2 more. Journal of Experimental Medicine, 2010

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Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen. Long-lived memory B cells and plasma cells are also generated in GCs, although how B cell differentiation in GCs is regulated is unclear. IL-21, secreted by T follicular helper cells, is important for adaptive immune responses, although there are conflicting reports on its target cells and mode of action in vivo. We show that the absence of IL-21 signaling profoundly affects the B cell response to protein antigen, reducing splenic and bone marrow plasma cell formation and GC persistence and function, influencing their proliferation, transition into memory B cells, and affinity maturation. Using bone marrow chimeras, we show that these activities are primarily a result of CD3-expressing cells producing IL-21 that acts directly on B cells. Molecularly, IL-21 maintains expression of Bcl-6 in GC B cells. The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype. IL-21 thus controls fate choices of GC B cells directly.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/e7dae0291199ab80bb51d2ee0d9c98d1bb0c4b53

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Citations in the corpus

Induction of ICOS+CXCR3+CXCR5+ TH Cells Correlates with Antibody Responses to Influenza Vaccination (2013, background): “TFH cells support the differentiation and survival of GC B cells (15, 16) through the secretion of interleukin-21 (IL-21) (17, 18).”
Follicular Helper T Cells. (2016, background): “In vivo, Tfh cell-derived IL-21, by maintaining BCL6 expression in GC B cells, controls the maintenance and optimal affinity maturation of the GC response (121, 122).”
Human Blood CXCR5+CD4+ T Cells Are Counterparts of T Follicular Cells and Contain Specific Subsets that Differentially Support Antibody Secretion (2011, background): “Thus, it is plausible that upon microbial invasion, CXCR5CD4 T cells draining into lymphoid organs interact with B cells presenting microbial antigens and induce their differentiation into Ig-producing cells or germinal center B cells through secretion of IL-21 (Linterman et al., 2010; MacLennan et ”
Bcl6 dependent T follicular helper cell differentiation diverges from effector cell differentiation during priming and depends on the gene Icos (2011, neutral): “…model has been challenged by studies that found normal Tfh cell differentiation in vivo in the absence of IL-6 or IL-21 (Poholek et al., 2010; Zotos et al., 2010), though partial defects were found in other studies (Linterman et al., 2010; Vogelzang et al., 2008), possibly because of reduced…”
PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells (2010, background): “Furthermore, it has been shown that IL-21 acts directly on GC B cells through the IL-21 receptor to affect GC B cell maintenance and the subsequent formation of PCs and is not required for the formation of T FH cell”