Human Typhi exposure generates differential multifunctional cross-reactive T-cell memory responses against Paratyphi and invasive nontyphoidal .

Objective: There are no vaccines for most of the major invasive strains causing severe infection in humans. We evaluated the specificity of adaptive T memory cell responses generated after Typhi exposure in humans against other major invasive strains sharing capacity for dissemination.

Methods: T memory cells from eleven volunteers who underwent controlled oral challenge with . Typhi were characterised by flow cytometry for cross-reactive cellular cytokine/chemokine effector responses or evidence of degranulation upon stimulation with autologous B-lymphoblastoid cells infected with either . Typhi, Paratyphi A (PA), . Paratyphi B (PB) or an invasive nontyphoidal strain of the . Typhimurium serovar (iNTSTy).

Results: Blood T-cell effector memory (T) responses after exposure to . Typhi in humans evolve late, peaking weeks after infection in most volunteers. Induced multifunctional CD4 Th1 and CD8 T cells elicited after . Typhi challenge were cross-reactive with PA, PB and iNTSTy. The magnitude of multifunctional CD4 T cell responses to . Typhi correlated with induction of cross-reactive multifunctional CD8 T cells against PA, PB and iNTSTy. Highly multifunctional subsets and T central memory and T effector memory cells that re-express CD45 (T) demonstrated less heterologous T-cell cross-reactivity, and multifunctional Th17 elicited after . Typhi challenge was not cross-reactive against other invasive .

Conclusion: Gaps in cross-reactive immune effector functions in human T-cell memory compartments were highly dependent on invasive strain, underscoring the importance of strain-dependent vaccination in the design of T-cell-based vaccines for invasive .