Th17 cell based vaccines in mucosal immunity

Abstract

Vaccination is proven to be effective in controlling many infections including small pox, influenza and hepatitis, but strain-specific factors may limit vaccine efficacy. All of these vaccines work through the generation of neutralizing antibodies but for some pathogens there may be roles for serotype-independent immunity. Recently several groups using murine vaccine models have shown that induced T helper cell responses including Th17 responses have shown the potential for CD4+ T-cell dependent vaccine responses. Th17 mediated protective responses involve the recruitment of neutrophils, release of anti-microbial peptides and IL-17-driven Th1 immunity. These effector mechanisms provide immunity against a range of pathogens including the recently described antibiotic-resistant metallo-beta-lactamase 1 Klebsiella pneumoniae. Continued elucidation of the mechanism of Th17 responses and identification of effective adjuvants for inducing robust non pathogenic Th17 responses may lead to successful Th17 based vaccines. Here we summarize the recent advances in understanding the role of Th17 in vaccine induced immunity. We also discuss the current status and future challenges in Th17-based mucosal vaccine development.

Figure 1. Proposed model of serotype dependent and independent immunity

Vaccination can induce both T cells dependent and independent immune responses. A) T cells independent antibody response generated by strong B cells receptor (BCR) signal by antigens and activation of both Toll-like receptor (TLR) and proinflammatory cytokine response. B) Dendritic cells derived IL-23 and IL-1β induce robust Th17 responses. IL-17 and IL-22 produced by Th17 cells activate epithelial cells mediated immune responses. Th17 targeted cytokines and chemokines (G-CSF and CXCL1) released from epithelial cells regulate neutrophils recruitment to the mucosal sites. Th17-mediated neutrophils response is reported to be essential for the protection against a range of pathogens. Epithelial cells also directly participate in limiting pathogens multiplication by the release of Th17 related cytokines regulated antimicrobial peptides. Apart from lymphotoxin signaling, Th17 cells involve in iBALT formation in the lung tissue by activating chemokines (CXCL13, CXCL19) released from the fibroblast. iBALT mediated local immune responses (both B and T cells response) are critical for clearance of influenza virus. Th17 cells also regulate late Th1 responses by modulating chemokines especially CXCL9, CXCL10 and CXCL11 response from epithelial cells. Th1-regulated cytokines (IFNγ or TNFα) and activation of macrophages are required for the immunity against M. tuberculosis. In addition, Th17 cells regulate polymeric immunoglobulin receptor (pIgR) expression on epithelial cells, which is essential for influx of B cells to the mucosal sites, however, the relevance of this pathway in Th17 mediated immunity is yet to determine.