Mechanisms of Cholera Toxin in the Modulation of TH17 Responses

Abstract

Numerous studies have shown that TH17 cells and their signature cytokine IL-17A are critical to host defense against various bacterial and fungal infections. The protective responses mediated by TH17 cells and IL-17A include the recruitment of neutrophils, release of antimicrobial peptides and chemokines, and enhanced tight junction of epithelial cells. Due to the importance of TH17 cells in infections, efforts have been made to develop TH17-based vaccines. The goal of vaccination is to establish a protective immunological memory. Most currently approved vaccines are antibody-based and have limited protection against stereotypically different strains. Studies show that T-cell–based vaccines may overcome this limitation and protect hosts against infection of different strains. Two main strategies are used to develop TH17 vaccines: identification of TH17-specific antigens and TH17-skewing adjuvants. Studies have revealed that cholera toxin (CT) induces a potent Th17 response following vaccination. Antigen vaccination along with CT induces a robust TH17 response, which is sometimes accompanied by TH1 responses. Due to the toxicity of CT, it is hard to apply CT in a clinical setting. Thus, understanding how CT modulates TH17 responses may lead to the development of successful TH17-based vaccines.

A Systemic Prime–Intrarectal Pull Strategy Raises Rectum-Resident CD8+ T Cells for Effective Protection in a Murine Model of LM-OVA Infection

“…In contrast, we showed that CXCL10 was less effective than CT as an adjuvant in the intrarectal pull step. A major mechanism behind CT's adjuvant activity is stimulating antigen-presenting cells for enhanced antigen presentation (24,41,42). This property of CT is consistent with our notion that the rectum homing of primed CD8+ T cells is mainly licensed by ligation to locally presented cognate antigens.…”

Sublingual immunization with Japanese encephalitis virus vaccine effectively induces immunity through both cellular and humoral immune responses in mice

“…administration. The cytokine IL‐17 has been implicated in regulation of inflammation and autoimmune diseases . It is notable that our recent data shows that mice immunized with ovalbumin in the absence of CT adjuvant produce lower antibody titers than those immunized in the presence of CT adjuvant (data not shown).…”

“…immunization requires mixing of CT with the vaccine to trigger an appropriate immune response. The mucosal adjuvant activity of CT involves induction of IL‐1 and other proinflammatory cytokines . Thus, we suspect that CT may nonspecifically trigger the induction of IL‐17; however, administration of CT alone did not induce IL‐17.…”

Direct Manipulation of T Lymphocytes by Proteins of Gastrointestinal Bacterial Pathogens

“…There has been significant interest in using CT and LT as adjuvants in vaccination, and understanding how it is able to steer T cell responses provides insight in how to better improve vaccination or to engineer nontoxic derivatives that are able to promote its adjuvancy (72)(73)(74)(75).…”