Attenuated Oral Typhoid Vaccine Ty21a Elicits Lamina Propria and Intra-Epithelial Lymphocyte Tissue-Resident Effector Memory CD8T Responses in the Human Terminal Ileum

Tissue-resident memory T cells (T-RM) are newly defined memory T cells (T-M) distinct from circulating T-M 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 T-RM 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 (T-RM) 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+ T-RM 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+ T-RM and CD8+CD69+CD103- T cells subsets were observed following Ty21a-immunization. However, LPMC CD8+ T-RM exhibited significantly higher levels of cytokines (IFN-gamma, IL-17A, and TNF-alpha) 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-gamma, IL-2, and IL-17A. Finally, we assessed CD8+ T-RM in IEL and observed that the frequency of IEL CD8+ T(RM )is significantly lower following Ty21a immunization. However, ex-vivo IEL CD8+ T-RM elicited by Ty21a immunization spontaneously produced significantly higher levels of cytokines (IFN-gamma, IL-17A, IL-2, and TNF-alpha). This study provides the first demonstration of the effect of oral Ty21a vaccination on CD8+ T(RM )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.