Effect of live oral attenuated Typhoid vaccine, Ty21a, on systemic and terminal ileum mucosal CD4+ T memory responses in humans

Abstract

Our current understanding of CD4+ T cell mediated immunity (CMI) elicited by the oral live attenuated typhoid vaccine Ty21a is primarily derived from studies using peripheral blood. Very limited data is available in humans regarding mucosal immunity (especially CD4+ T) at the site of infection (e.g., terminal ileum; TI). Here using multiparametric flow cytometry, we examined the effect of Ty21a immunization on TI lamina propria mononuclear cells (LPMC) and peripheral blood CD4+ T memory (T_M) subsets in volunteers undergoing routine colonoscopy. Interestingly, we observed significant increases in the frequencies of LPMC CD4+ T cells following Ty21a-immunization, restricted to the T-effector/memory (T_EM)-CD45RA+ (T_EMRA) subset. Importantly, Ty21a-immunization elicited S. Typhi responsive LPMC CD4+ T cells in all major T_M subsets (interferon (IFN) and interleukin (IL)-17A in T effector/memory -T_EM-; IFN and macrophage inflammatory protein (MIP)-1 in T central/memory -T_CM-; and IL-2 in T_EMRA). Subsequently, we analyzed LPMC S. Typhi responsive CD4+ T cells in depth for multifunctional (MF) effectors. We found that LPMC CD4+ T_EM responses were mostly MF, except for those cells exhibiting the characteristics associated with IL-17A responses. Finally, we compared mucosal to systemic responses and observed that LPMC CD4+ S. Typhi-specific responses were unique and distinct from their systemic counterparts. This study provides the first demonstration of S. Typhi-specific CD4+ T_M responses in the human terminal ileum mucosa and provides valuable information about the generation of mucosal immune responses following oral Ty21a-immunization.