Figure 12.

Drawing depicting S Typhi–specific responses elicited in the TI mucosa and peripheral blood (PBMC) following Ty21a immunization in humans. Following oral immunization with the attenuated vaccine strain Ty21a, these bacteria enter the host by various mechanisms (eg, M-cell adhesion, epithelial invasion, and dendritic cells luminal capture) and are presented by antigen-presenting cells (ie, macrophages, dendritic cells) to immune cells (ie, CD8⁺-T_M) in the lamina propria (LP) compartment or draining mesenteric lymph nodes. CD8⁺-T_M are subsequently activated to produce higher levels of cytokines/chemokines (IFNγ, TNFα, IL-2, IL-17A, and MIP1β) and increased cytotoxicity (upregulation of CD107a). Following Ty21a immunization each major CD8⁺-T_M (T_EM, T_CM and, T_EMRA) subset acquires unique characteristics in the TI LP. CD8⁺-T_EM responses include S and MF cells. LP cytotoxic responses (CD107⁺) were observed both as S and MF cells, whereas the other responses were observed largely as MF cells. The relationship between mucosal and systemic immunity focused on CD8⁺-T_EM responses are also depicted in this drawing. Following Ty21a immunization, PBMC CD8⁺-T_EM are modulated to produce cytokines/chemokines and upregulate cytotoxic responses. However, peripheral blood CD8⁺-T_EM responses elicited are induced mostly as MF cells rather than single producing cells. Of note, significant correlations were observed between LPMC and PBMC for all tested MF CD8⁺-T_EM responses except for IL2. These results suggest that CD8⁺-T_EM MF effectors elicited by immunization are the main populations with the capacity to shuttle between the TI mucosa and peripheral blood. CD8⁺-T_EM in the terminal ileum can be composed of various subsets including tissue-resident memory T cells (T_RM) and other CD8⁺ T cell subsets. Additionally, CD8⁺ T_EM MF represent 64 different combinations of effector subtypes defined by the expression of CD107a, IFN-γ, IL-17A, TNF-α, IL-2, and/or MIP-1β, including doublet to sextuplet subtypes. This adds another layer of complexity in defining effector responses. This is illustrated in the figure by showing, for example, CD8⁺ T_EM MF quadruplets (subset CD107a⁺, IL17A⁺, TNF-α⁺, and MIP-1β⁺), which exhibited significantly higher responses in terminal ileum LPMC than in PBMC following Ty21a immunization. Trends toward Ty21a vaccinees exhibiting higher responses than unvaccinated volunteers are denoted with black arrows. Significantly higher responses in Ty21a vaccinees than in unvaccinated volunteers are denoted with a red asterisk. Trends toward TI-LPMC showing higher responses than PBMC are denoted with red arrows. Significantly higher responses in TI-LPMC compared with PBMC are denoted with blue upward arrows. Significantly lower responses in TI-LPMC compared with PBMC are denoted with blue downward arrows.