title: IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation.
abstract: Cytokines are important modulators of lymphocytes, and both interleukin-21 (IL-21) and IL-6 have proposed roles in T follicular helper (Tfh) differentiation, and directly act on B cells. Here we investigated the absence of IL-6 alone, IL-21 alone, or the combined lack of IL-6 and IL-21 on Tfh differentiation and the development of B cell immunity in vivo. C57BL/6 or IL-21(-/-) mice were treated with a neutralizing monoclonal antibody against IL-6 throughout the course of an acute viral infection (lymphocytic choriomeningitis virus, LCMV). The combined absence of IL-6 and IL-21 resulted in reduced Tfh differentiation and reduced Bcl6 protein expression. In addition, we observed that these cytokines had a large impact on antigen-specific B cell responses. IL-6 and IL-21 collaborate in the acute T-dependent antiviral antibody response (90% loss of circulating antiviral IgG in the absence of both cytokines). In contrast, we observed reduced germinal center formation only in the absence of IL-21. Absence of IL-6 had no impact on germinal centers, and combined absence of both IL-21 and IL-6 revealed no synergistic effect on germinal center B cell development. Studying CD4 T cells in vitro, we found that high IL-21 production was not associated with high Bcl6 or CXCR5 expression. TCR stimulation of purified naïve CD4 T cells in the presence of IL-6 also did not result in Tfh differentiation, as determined by Bcl6 or CXCR5 protein expression. Cumulatively, our data indicates that optimal Tfh formation requires IL-21 and IL-6, and that cytokines alone are insufficient to drive Tfh differentiation.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
authors.forename: Danelle
authors.initials: D
authors.lastname: Eto
authors.forename: Christopher
authors.initials: C
authors.lastname: Lao
authors.forename: Daniel
authors.initials: D
authors.lastname: DiToro
authors.forename: Burton
authors.initials: B
authors.lastname: Barnett
authors.forename: Tania C
authors.initials: TC
authors.lastname: Escobar
authors.forename: Robin
authors.initials: R
authors.lastname: Kageyama
authors.forename: Isharat
authors.initials: I
authors.lastname: Yusuf
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D006801:Humans; D007109:Immunity / Q000276:immunology*; D015850:Interleukin-6 / Q000172:deficiency / Q000378:metabolism*; D007378:Interleukins / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D015850:Interleukin-6; D007378:Interleukins; D000098546:Interleukin-21