Broad systemic T cell immunity to Salmonella enterica serovar Typhi in U.S. healthy adults

Abstract

T cell mediated immunity (T-CMI) is an important component of effective host immunity against intracellular pathogens such as Salmonella enterica serovar Typhi ( S. Typhi; ST). Baseline T-CMI responsiveness to S. Typhi has been previously described in healthy individuals, likely reflecting cross-reactive responsiveness to other Enterobacteriaceae within the gut microbiota. Interestingly, T cell baseline responsiveness has been associated with protection or susceptibility in a human challenge model following exposure to wild-type (wt) ST. To better understand the contribution of this baseline responsiveness to immunity against ST infection, an in-depth characterization of T cell immunity is needed. Here, peripheral blood mononuclear cells from eighteen healthy volunteers with no history of typhoid fever vaccination or infection were co-cultured with autologous B-lymphoblastoid cell lines (B-LCL) previously infected with wt ST as antigen presenting cells. Non-infected B-LCL (NI) were used as controls. After 18 h or 40 h of stimulation, cells were stained with a 52-parameter mass cytometry antibody panel and analyzed using manual gating, dimensionality reduction and unsupervised clustering approaches. We studied conventional CD4 + and CD8 + T memory cells, including T effector memory (T EM ), T EM re-expressing CD45RA (T EMRA ), and T central memory (T CM ), CD4 + and CD8 + T stem cell memory (T SCM ), CD4 + circulating T follicular helper (cT FH ), CD4 + T regulatory (T reg ), and CD8 + T regulatory precursors (T rp ), as well as non-conventional CD8 + mucosal associated invariant T (MAIT), T gamma delta (Tγδ), and Natural-Killer T (NKT) cells. All studied cell subsets showed significant (p<0.01) baseline responsiveness to ST-infected target cells when compared to NI target cells. Most functional responses were observed in activation, homing, and cytotoxicity markers across all conventional and non-conventional T cell subsets, defining in great depth the characteristics of baseline T-CMI to S. Typhi. This high-dimensional approach showed a complex interaction between distinct cell subsets with multifunctional properties and extended previous insights into the baseline T-CMI to S. Typhi. This will help guide future investigations of immunity in healthy individuals following infection or vaccination.