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Oral typhoid vaccine Ty21a elicits antigen-specific resident memory CD4+ T cells in the human terminal ileum lamina propria and epithelial compartments.

ABSTRACT: BACKGROUND:Salmonella enterica serovar Typhi (S. Typhi) is a highly invasive bacterium that infects the human intestinal mucosa and causes ~?11.9-20.6 million infections and ~?130,000-223,000 deaths annually worldwide. Oral typhoid vaccine Ty21a confers a moderate level of long-lived protection (5-7 years) in the field. New and improved vaccines against enteric pathogens are needed but their development is hindered by a lack of the immunological correlates of protection especially at the site of infection. Tissue resident memory T (TRM) cells provide immediate adaptive effector immune responsiveness at the infection site. However, the mechanism(s) by which S. Typhi induces TRM in the intestinal mucosa are unknown. Here, we focus on the induction of S. Typhi-specific CD4+TRM subsets by Ty21a in the human terminal ileum lamina propria and epithelial compartments. METHODS:Terminal ileum biopsies were obtained from consenting volunteers undergoing routine colonoscopy who were either immunized orally with 4 doses of Ty21a or not. Isolated lamina propria mononuclear cells (LPMC) and intraepithelial lymphocytes (IEL) CD4+TRM immune responses were determined using either S. Typhi-infected or non-infected autologous EBV-B cell lines as stimulator cells. T-CMI was assessed by the production of 4 cytokines [interferon (IFN)?, interleukin (IL)-2, IL-17A and tumor necrosis factor (TNF)?] in 36 volunteers (18 vaccinees and 18 controls volunteers). RESULTS:Although the frequencies of LPMC CD103+ CD4+TRM were significant decreased, both CD103+ and CD103- CD4+TRM subsets spontaneously produced significantly higher levels of cytokines (IFN? and IL-17A) following Ty21a-immunization. Importantly, we observed significant increases in S. Typhi-specific LPMC CD103+ CD4+TRM (IFN? and IL-17A) and CD103- CD4+TRM (IL-2 and IL-17A) responses following Ty21a-immunization. Further, differences in S. Typhi-specific responses between these two CD4+TRM subsets were observed following multifunctional analysis. In addition, we determined the effect of Ty21a-immunization on IEL and observed significant changes in the frequencies of IEL CD103+ (decrease) and CD103- CD4+TRM (increase) following immunization. Finally, we observed that IEL CD103- CD4+TRM, but not CD103+ CD4+TRM, produced increased cytokines (IFN?, TNF? and IL-17A) to S. Typhi-specific stimulation following Ty21a-immunization. CONCLUSIONS:Oral Ty21a-immunization elicits distinct compartment specific immune responses in CD4+TRM (CD103+ and CD103-) subsets. This study provides novel insights in the generation of local vaccine-specific responses. Trial registration This study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifier NCT03970304, Registered 29 May 2019-Retrospectively registered, http://www.ClinicalTrials.gov/NCT03970304).

SUBMITTER: Booth JS

PROVIDER: S-EPMC7043047 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Oral typhoid vaccine Ty21a elicits antigen-specific resident memory CD4<sup>+</sup> T cells in the human terminal ileum lamina propria and epithelial compartments.

Booth Jayaum S JS Goldberg Eric E Barnes Robin S RS Greenwald Bruce D BD Sztein Marcelo B MB

Journal of translational medicine 20200225 1

<h4>Background</h4>Salmonella enterica serovar Typhi (S. Typhi) is a highly invasive bacterium that infects the human intestinal mucosa and causes ~ 11.9-20.6 million infections and ~ 130,000-223,000 deaths annually worldwide. Oral typhoid vaccine Ty21a confers a moderate level of long-lived protection (5-7 years) in the field. New and improved vaccines against enteric pathogens are needed but their development is hindered by a lack of the immunological correlates of protection especially at the ...[more]

PMID: 32098623

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Project description:Tissue-resident memory T cells (TRM) are newly defined memory T cells (TM) distinct from circulating TM subsets which have the potential to mount rapid protective immune responses at the site of infection. However, very limited information is available regarding the role and contribution of TRM in vaccine-mediated immune responses in humans at the site of infection. Here, we studied the role and contribution of tissue resident memory T cells (TRM) located in the terminal ileum (TI) (favored site of infection for S. Typhi) following oral Ty21a immunization in humans. We examined TI-lamina propria mononuclear cells (LPMC) and intra-epithelial lymphocytes (IEL) CD8+ TRM subsets obtained from healthy volunteers undergoing medically-indicated colonoscopies who were either immunized with Ty21a or unvaccinated. No significant differences in the frequencies of LPMC CD8+ TRM and CD8+CD69+CD103- T cells subsets were observed following Ty21a-immunization. However, LPMC CD8+ TRM exhibited significantly higher levels of cytokines (IFN-γ, IL-17A, and TNF-α) ex-vivo in Ty21a-vaccinated than in unvaccinated volunteers. LPMC CD8+ TRM S. Typhi-specific responses were evaluated using S. Typhi-infected targets and found to produce significantly higher levels of S. Typhi-specific IL-17A. In contrast, LPMC CD8+CD69+CD103- T cells produced significantly increased S. Typhi-specific levels of IFN-γ, IL-2, and IL-17A. Finally, we assessed CD8+ TRM in IEL and observed that the frequency of IEL CD8+ TRM is significantly lower following Ty21a immunization. However, ex-vivo IEL CD8+ TRM elicited by Ty21a immunization spontaneously produced significantly higher levels of cytokines (IFN-γ, IL-17A, IL-2, and TNF-α). This study provides the first demonstration of the effect of oral Ty21a vaccination on CD8+ TRM subsets (spontaneous and S. Typhi-specific) responses in the LPMC and IEL compartment of the human terminal ileum mucosa, contributing novel information to our understanding of the generation of mucosal immune responses following oral Ty21a-immunization.

Project description:BackgroundThe impact of aging on the immune system is unequivocal and results in an altered immune status termed immunosenescence. In humans, the mechanisms of immunosenescence have been examined almost exclusively in blood. However, most immune cells are present in tissue compartments and exhibit differential cell (e.g., memory T cells -TM) subset distributions. Thus, it is crucial to understand immunosenescence in tissues, especially those that are exposed to pathogens (e.g., intestine). Using a human model of oral live attenuated typhoid vaccine, Ty21a, we investigated the effect of aging on terminal ileum (TI) tissue resident memory T (TRM) cells. TRM provide immediate adaptive effector immune responsiveness at the infection site. However, it is unknown whether aging impacts TRM S. Typhi-responsive cells at the site of infection (e.g., TI). Here, we determined the effect of aging on the induction of TI S. Typhi-responsive TRM subsets elicited by Ty21a immunization.ResultsWe observed that aging impacts the frequencies of TI-lamina propria mononuclear cells (LPMC) TM and TRM in both Ty21a-vaccinated and control groups. In unvaccinated volunteers, the frequencies of LPMC CD103- CD4+ TRM displayed a positive correlation with age whilst the CD4/CD8 ratio in LPMC displayed a negative correlation with age. We observed that elderly volunteers have weaker S. Typhi-specific mucosal immune responses following Ty21a immunization compared to adults. For example, CD103+ CD4+ TRM showed reduced IL-17A production, while CD103- CD4+ TRM exhibited lower levels of IL-17A and IL-2 in the elderly than in adults following Ty21a immunization. Similar results were observed in LPMC CD8+ TRM and CD103- CD8+ T cell subsets. A comparison of multifunctional (MF) profiles of both CD4+ and CD8+ TRM subsets between elderly and adults also showed significant differences in the quality and quantity of elicited single (S) and MF responses.ConclusionsAging influences tissue resident TM S. Typhi-specific responses in the terminal ileum following oral Ty21a-immunization. This study is the first to provide insights in the generation of local vaccine-specific responses in the elderly population and highlights the importance of evaluating tissue immune responses in the context of infection and aging.Trial registrationThis study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifier NCT03970304 , Registered 29 May 2019 - Retrospectively registered).

Dataset Information

Oral typhoid vaccine Ty21a elicits antigen-specific resident memory CD4+ T cells in the human terminal ileum lamina propria and epithelial compartments.

Publications

Oral typhoid vaccine Ty21a elicits antigen-specific resident memory CD4<sup>+</sup> T cells in the human terminal ileum lamina propria and epithelial compartments.

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