T Helper 17 Promotes Induction of Antigen-Specific Gut-Mucosal Cytotoxic T Lymphocytes following Adenovirus Vector Vaccination

Abstract

Few current vaccines can establish antigen (Ag)-specific immune responses in both mucosal and systemic compartments. Therefore, development of vaccines providing defense against diverse infectious agents in both compartments is of high priority in global health. Intramuscular vaccination of an adenovirus vector (Adv) has been shown to induce Ag-specific cytotoxic T lymphocytes (CTLs) in both systemic and gut-mucosal compartments. We previously found that type I interferon (IFN) signaling is required for induction of gut-mucosal, but not systemic, CTLs following vaccination; however, the molecular mechanism involving type I IFN signaling remains unknown. Here, we found that T helper 17 (Th17)-polarizing cytokine expression was down-regulated in the inguinal lymph nodes (iLNs) of Ifnar2−/− mice, resulting in the reduction of Ag-specific Th17 cells in the iLNs and gut mucosa of the mice. We also found that prior transfer of Th17 cells reversed the decrease in the number of Ag-specific gut-mucosal CTLs in Ifnar2−/− mice following Adv vaccination. Additionally, prior transfer of Th17 cells into wild-type mice enhanced the induction of Ag-specific CTLs in the gut mucosa, but not in systemic compartments, suggesting a gut mucosa-specific mechanism where Th17 cells regulate the magnitude of vaccine-elicited Ag-specific CTL responses. These data suggest that Th17 cells translate systemic type I IFN signaling into a gut-mucosal CTL response following vaccination, which could promote the development of promising Adv vaccines capable of establishing both systemic and gut-mucosal protective immunity.

The protective and pathogenic roles of IL-17 in viral infections: friend or foe?

“…To examine the function of IL-17 during RSV infection, they found that exogenous IL-17 administration to RSV-challenged neonatal mice led to a decreased lung inflammation profile, while IL-17 neutralization in adults caused increased inflammation and airway mucus [64]. Consistent with this finding, in SIV-infected rhesus macaques, the percentage of mucosal Th17 cells is negatively correlated with plasma SIV levels, with Th1 cell number predominating over that of Th17 cells in highly viraemic animals [40]. Moreover, during and after antiretroviral therapy, Th17 cell function and frequency were negatively associated with both systemic inflammation and virus persistence [65].…”

“…It has been observed that a higher Th17 percentage is associated with increased T-cell proliferation and more potent simian immunodeficiency virus (SIV)-specific CTL responses in SIV-infected rhesus macaques [38,39]. In this model, prior transfer of Th17 cells was shown to enhance the induction of antigen-specific CTLs following vaccination with an adenovirus vector [40]. Thus, the development of IL-17-based therapeutic strategies and vaccines will be of particular future importance.…”

In Vitro Th17-Polarized Human CD4+ T Cells Exacerbate Xenogeneic Graft-versus-Host Disease

“…However, we did not observe higher chimerism in PB at days +14 and +21 in Th17 coinjected mice. Data from antitumor and antiviral immunity experiments have also revealed that Th17 cells could have a unique ability to promote CD8 + T cell priming and cytotoxicity in target tissues through both direct [52][53][54] and indirect (via the recruitment of dendritic cells) [52,55] mechanisms.…”

Anti-ICOS mAb Targets Pathogenic IL-17A-expressing Cells in Canine Model of Chronic GVHD

“…Both ICOS signaling and IL-17A have been implicated in mediating increased persistence and cytotoxicity of CD8 + cells. 10,[33][34][35][36] Therefore, the increase in CD4 + ICOS + and ICOS + IL-17A + cells in chronic GVHD may be responsible for the increase in CD8 + GranzymeB + cells, suggesting that targeting the CD4 + ICOS + population may directly affect CD4 + cells and indirectly affect CD8 + cells. Anti-ICOS mAb was not expected to target CD8 + cells directly since a greater proportion of ICOS + cells are CD4 + , and CD8+ cells preferentially use an alternate costimulatory receptor, 4-1BB, to enhance expansion and survival.…”