Interleukin (IL)-21 promotes intestinal IgA response to microbiota

Abstract

Commensal microbiota-specific Th17 cells are enriched in the intestines, which can convert into Tfh in Peyer’s patches, and are crucial for production of intestinal IgA against microbiota, however, the role of Th17 and Tfh cytokines in regulating the mucosal IgA response to enteric microbiota is still not completely known. In this study, we found that intestinal IgA was impaired in mice deficient in IL-17 or IL-21 signaling. IL-21, but not IL-17, is able to augment B cell differentiation to IgA+ cells as mediated by TGFβ1, and accelerate IgA class switch recombination (CSR). IL-21 and retinoic acid (RA) induce IgA+ B cell development and IgA production, and drives autocrine TGFβ1 production to initiate IgA CSR. Repletion of T cell-deficient TCRβxδ−/− mice with Th17 cells specific for commensal bacterial antigen, increased levels of IgA+ B cells and IgA production in the intestine, which was blocked by neutralizing IL-21. Thus, IL-21 functions to strongly augment IgA production under intestinal environment. Furthermore, IL-21 promotes intestinal B cell homing through α4β7 expression, alone or with TGFβ and RA. Together, IL-21 from microbiota-specific Th17 and/or Tfh cells contributes to robust intestinal IgA levels by enhancing IgA+ CSR, IgA production, and B cell trafficking into the intestine.

Tumor-Elicited Inflammation and Colorectal Cancer

“…IL-21 augments Th2 function and is important for B cell development (Cao et al, 2015;Ozaki et al, 2002Ozaki et al, , 2004Pesce et al, 2006). IL-21 is produced by Th17 cells and acts in an autocrine manner to boost Th17 differentiation (Korn et al, 2007;Nurieva et al, 2007).…”

Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems

“…B cells can undergo Ig class switch recombination (CSR) and acquire the ability to produce IgA after CD40-CD40L ligation in the presence of TGF- β with contribution from other cytokines including IL-4, IL-5, IL-6, IL-10, and IL-21 (5–8) (Figure 1). Other costimulatory signals such as B cell-activating factor of the TNF family (BAFF), a proliferation-inducing ligand (APRIL), retinoic acid (RA), and nitric oxide also facilitate CSR for the production of IgA (7, 9, 10).…”

“…Among these cells, follicular T helper (Tfh) cells (17) play a key role in both immunoglobulin CSR and somatic hypermutation in antigen recognizing regions and subsequent generation of high-affinity antibody producing plasma cells and memory B cells. The expression of CXCR5 by Tfh cells allow them to locate into B cell follicles, where they produce IL-21, an IgA promoting cytokine (5). Tfh were reported to differentiate from other Th cell subsets suggesting a plasticity of mucosal T cells and potential for rapid adaptation to the luminal environment and ultimately produce the mucosal IgA Abs needed to maintain homeostasis.…”

“…Cytokines such as IL-5 and IL-6 enhance the effect of RA on α4β7. The cytokine IL-21 was shown to induce the expression of the gut-homing receptor α4β7, an effect enhanced by TGFβ1 and RA (5). The chemokine receptor CCR9 together with α4β7 represent the best-described factors regulating homing of immune cells into the gut (43).…”

Biological effects of IL-21 on different immune cells and its role in autoimmune diseases

“…IL-21 can induce isotype class switch to IgA in CD40-stimulated human naive B cells; but this induction is inhibited by IL-4 (32). It was also reported that IL-21 can induce IgA isotype switching and also plasma cells homing to mucosal sites by synergistically interacting with transforming growth factor-β (TGFβ) suggesting that the impact of IL-21 on immunoglobulin production may be dependent on other interacting cytokines and a specific stage of B cell differentiation in vivo (18,33,34).…”