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.
Highlights
Most infectious agents enter the body via the extensive surface areas of mucosal membranes; development of vaccines capable of establishing protective immunity in both mucosal and systemic compartments is a high-priority global health issue [1, 2]
T cell priming occurred in inguinal lymph nodes (iLNs) acting as draining lymph nodes for the vaccination sites, resulting in the induction of Ag-specific cytotoxic T lymphocytes (CTLs)
We confirmed that the frequencies of Ag-specific CTLs among total CTLs in iLNs were similar in WT and Ifnar2−/− mice (Figure 1A), suggesting that T cell priming was induced in these mice
Summary
Most infectious agents enter the body via the extensive surface areas of mucosal membranes; development of vaccines capable of establishing protective immunity in both mucosal and systemic compartments is a high-priority global health issue [1, 2]. Replication-incompetent recombinant adenovirus vectors (Advs) have advantages as gene therapy vectors. They provide the highest gene transduction efficiency among currently available vectors, exhibit low levels of genotoxicity because they are not integrated into chromosomal DNA, and can be prepared at high titers. Previous reports showed that intramuscular (i.m.) immunization with Adv vaccines expressing simian immunodeficiency virus (SIV) proteins induced protective and durable SIV Ag-specific cytotoxic T lymphocytes (CTLs) in both gut-mucosal and systemic sites, in mice and rhesus macaques [8,9,10]. To generate more protective Adv vaccines, it is necessary to identify the mechanisms involved in Adv-vaccine establishment of both systemic and gut-mucosal immunity
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