The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells

Abstract

Interleukin (IL) 6 is a proinfl ammtory cytokine produced by antigen-presenting cells and nonhematopoietic cells in response to external stimuli. It was initially identifi ed as a B cell growth factor and inducer of plasma cell differentiation in vitro and plays an important role in antibody production and class switching in vivo. However, it is not clear whether IL-6 directly affects B cells or acts through other mechanisms. We show that IL-6 is suffi cient and necessary to induce IL-21 production by naive and memory CD4 + T cells upon T cell receptor stimulation. IL-21 production by CD4 + T cells is required for IL-6 to promote B cell antibody production in vitro. Moreover, administration of IL-6 with inactive infl uenza virus enhances virus-specifi c antibody production, and importantly, this effect is dependent on IL-21. Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4 + T cells through increased IL-21 production. IL-6 could therefore be a potential coadjuvant to enhance humoral immunity.

Expansion of Tfh‐like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88‐deficient mice

“…4) suggest that CD11b 1 Gr-1 1 inflammatory myeloid cells might regulate the generation of CD4 1 Tfh-like cells. Furthermore, CD11b 1 Gr-1 1 inflammatory myeloid cells produced IL-6, one candidate cytokine for Tfh-cell differentiation [37,38], and also expressed ICOSL and PD-L1. However, the requirement of IL-6 for Tfh cell development in vivo is still controversial [38], and IL-6 might influence B-cell activation T-cell-independent manner.…”

Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling

“…Moreover, IL-6 is a immunomodulatory cytokine that was systemically high in the serum. It controls plasma B-cell differentiation, and it influences also T helper cell cytokine production through Stat3-dependent signaling (1,(25)(26)(27). Stat3 isoforms are known to cooperate with c-Jun or JunD proteins specifically (33).…”

“…S4 I and E), indicating that G-CSF is not responsible for the autoimmune phenotype. IL-6-Jak1-Stat3 activation promotes plasma B-cell differentiation either directly (26) or indirectly through CD4 ϩ T helper cells (27). To investigate the role of lymphocytes in the development of local and systemic autoimmune alterations, JunB ⌬ep mice were crossed with Rag2 Ϫ/Ϫ mice.…”

In vivo effects of the anti–interleukin‐6 receptor inhibitor tocilizumab on the B cell compartment

“…In vitro studies in IL-6-knockout mice have shown a marked reduction in B cell immune responses (7), particularly reductions in the levels of IgG1, IgG2a, and IgG3 upon immunization with a T cell-dependent antigen (8), suggesting that IL-6 is central for the induction and/or maintenance of plasma cells that produce these immunoglobulin subclasses. A recent study showed that antibody production is indirectly promoted by B cell helper capabilities of CD4ϩ T cells through increased IL-21 production upon IL-6 stimulation (9).…”