Dataset Information

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.

SUBMITTER: Hemmi M

PROVIDER: S-EPMC5681732 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Hemmi Masahisa M Tachibana Masashi M Fujimoto Natsuki N Shoji Masaki M Sakurai Fuminori F Kobiyama Kouji K Ishii Ken J KJ Akira Shizuo S Mizuguchi Hiroyuki H

Frontiers in immunology 20171106

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 requ ...[more]

PMID: 29163524

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Project description:Modified Vaccinia virus Ankara (MVA) is an attenuated strain of vaccinia virus and currently under investigation as a promising vaccine vector against infectious diseases and cancer. MVA acquired mutations in host range and immunomodulatory genes, rendering the virus deficient for replication in most mammalian cells. MVA has a high safety profile and induces robust immune responses. However, the role of innate immune triggers for the induction of cytotoxic T cell responses after vaccination is incompletely understood. Stimulator of interferon genes (STING) is an adaptor protein which integrates signaling downstream of several DNA sensors and therefore mediates the induction of type I interferons and other cytokines or chemokines in response to various dsDNA viruses. Since the type I interferon response was entirely STING-dependent during MVA infection, we studied the effect of STING on primary and secondary cytotoxic T cell responses and memory T cell formation after MVA vaccination in STING KO mice. Moreover, we analyzed the impact of STING on the maturation of bone marrow-derived dendritic cells (BMDCs) and their functionality as antigen presenting cells for cytotoxic T cells during MVA infection in vitro. Our results show that STING has an impact on the antigen processing and presentation capacity of conventionel DCs and played a crucial role for DC maturation and type I interferon production. Importantly, STING was required for the induction of efficient cytotoxic T cell responses in vivo, since we observed significantly decreased short-lived effector and effector memory T cell responses after priming in STING KO mice. These findings indicate that STING probably integrates innate immune signaling downstream of different DNA sensors in DCs and shapes the cytotoxic T cell response via the DC maturation phenotype which strongly depends on type I interferons in this infection model. Understanding the detailed functions of innate immune triggers during MVA infection will contribute to the optimized design of MVA-based vaccines.

Dataset Information

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

Publications

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

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