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

By M. Linterman, L. Beaton, Di Yu, Roybel R. Ramiscal, Monika Srivastava, Jennifer J. Hogan, N. Verma, M. Smyth, R. Rigby, Carola G. Vinuesa. Journal of Experimental Medicine, 2010

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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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/2841ea509e2b58664268d7fae6d88d5bee5c13ff

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Citations in the corpus

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”
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): “…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 maintenance of Tfh cells (Linterman et al., 2010).”