Th17 Cells Upregulate Polymeric Ig Receptor and Intestinal IgA and Contribute to Intestinal Homeostasis

Abstract

Although enriched in normal intestines, the role of CD4+ Th17 cells in regulation of the host response to microbiota, and whether and how they contribute to intestinal homeostasis is still largely unknown. It is also unclear whether Th17 cells regulate intestinal IgA production, which is also abundant in the intestinal lumen and plays a crucial role as the first defense line in host response to microbiota. In this study, we found that intestinal polymeric Ig receptor (pIgR) and IgA production was impaired in T cell-deficient TCRβxδ−/− mice. Repletion of TCRβxδ−/− mice with Th17 cells from CBir1 flagellin TCR transgenic mice, which are specific for a commensal antigen, increased intestinal pIgR and IgA. The levels of intestinal pIgR and IgA in B6.IL-17 receptor (IL-17R−/−) mice were lower than wild-type mice. Treatment of colonic epithelial HT-29 cells with IL-17 increased pIgR expression. IL-17R−/− mice demonstrated systemic anti-microflora antibody response. Consistently, administering dextran sulfate sodium (DSS) to C57BL/6 mice after treatment with IL-17-neutralizing antibody resulted in more severe intestinal inflammation as compared to control antibody. Administering DSS to IL-17R−/− mice resulted in increased weight loss and more severe intestinal inflammation compared to wild-type mice, indicating a protective role of Th17 cells in intestinal inflammation. Individual mice with lower levels of pIgR and intestinal secreted IgA correlated with increased weight loss at the end of DSS administration. Collectively, our data reveal that microbiota-specific Th17 cells contribute to intestinal homeostasis by regulating intestinal pIgR expression and IgA secretion.

A Double Mutant Heat-Labile Toxin from Escherichia coli, LT(R192G/L211A), Is an Effective Mucosal Adjuvant for Vaccination against Helicobacter pylori Infection

“…Effective induction of IL-17 is desirable when designing a vaccine against H. pylori infection, since one of the functions of IL-17 is to recruit neutrophils, which have been shown to be essential in reducing the bacterial loads in the stomachs of vaccinated mice (28), although DeLyria et al have reported that in mice immunized with H. pylori lysate antigens and CT, neutrophils can be recruited to the stomach after challenge independent of IL-17A (29). However, IL-17 has multiple roles, and we believe that its main function in H. pylori infection is to promote bacterial clearance by possibly recruiting bactericidal neutrophils and also to stimulate local IgA antibody formation (30). We noted that vaccination with H. pylori antigens together with either dmLT or CT as an adjuvant was associated with enhanced inflammation in the stomach (postimmunization gastritis) after challenge with live bacteria.…”

Re-thinking the functions of IgA+plasma cells

“…[27][28][29] Several CD4 C T cell subsets have been implicated in germinal center (GC)-driven IgA responses including T-regulatory cells (Treg), 30 T-follicular helper cells (T FH ) 31 and Th17 cells. 32,33 It is likely that the generation of IgA C PC depends on the nature of the Ag and the location of where B cells are primed. Moreover, the precise combination of different leukocyte and mesenchymal cell types might influence the generation of IgA C PC.…”

Control of Giardiasis by Interleukin-17 in Humans and Mice—Are the Questions All Answered?

“…Similar to the previous paper by Dreesen et al, they showed that mice lacking IL-17RA were also defective in the control of G. muris infections and bone marrow chimeras indicated that the receptor was required on hematopoietic cells to mediate an effective antiparasitic effect. Additional comparisons of wild-type and IL-17A-deficient animals found that mice lacking IL-17A had significantly reduced fecal IgA levels both before and after infection, consistent with a role for IL-17 in inducing expression of the poly-Ig receptor that transports IgA from the serum into the intestinal lumen (15). IL-17A-deficient mice also had lower levels of mRNA encoding ␤-defensin-1, and IL-17RA-deficient mice had lower levels of mRNAs for resistin-like molecule ␤ (RELM-␤), serum amyloid A1 (Saa1), and serum amyloid A2 (Saa2), all proteins with potential antimicrobial and immunoregulatory functions (16)(17)(18)(19)(20).…”