Oral typhoid vaccine Ty21a elicits antigen-specific resident memory CD4+ T cells in the human terminal ileum lamina propria and epithelial compartments

Jayaum S Booth, Eric Goldberg, Robin S Barnes, Bruce D Greenwald, Marcelo B Sztein, Jayaum S Booth, Eric Goldberg, Robin S Barnes, Bruce D Greenwald, Marcelo B Sztein

Abstract

Background: Salmonella enterica serovar Typhi (S. Typhi) is a highly invasive bacterium that infects the human intestinal mucosa and causes ~ 11.9-20.6 million infections and ~ 130,000-223,000 deaths annually worldwide. Oral typhoid vaccine Ty21a confers a moderate level of long-lived protection (5-7 years) in the field. New and improved vaccines against enteric pathogens are needed but their development is hindered by a lack of the immunological correlates of protection especially at the site of infection. Tissue resident memory T (TRM) cells provide immediate adaptive effector immune responsiveness at the infection site. However, the mechanism(s) by which S. Typhi induces TRM in the intestinal mucosa are unknown. Here, we focus on the induction of S. Typhi-specific CD4+TRM subsets by Ty21a in the human terminal ileum lamina propria and epithelial compartments.

Methods: Terminal ileum biopsies were obtained from consenting volunteers undergoing routine colonoscopy who were either immunized orally with 4 doses of Ty21a or not. Isolated lamina propria mononuclear cells (LPMC) and intraepithelial lymphocytes (IEL) CD4+TRM immune responses were determined using either S. Typhi-infected or non-infected autologous EBV-B cell lines as stimulator cells. T-CMI was assessed by the production of 4 cytokines [interferon (IFN)γ, interleukin (IL)-2, IL-17A and tumor necrosis factor (TNF)α] in 36 volunteers (18 vaccinees and 18 controls volunteers).

Results: Although the frequencies of LPMC CD103+ CD4+TRM were significant decreased, both CD103+ and CD103- CD4+TRM subsets spontaneously produced significantly higher levels of cytokines (IFNγ and IL-17A) following Ty21a-immunization. Importantly, we observed significant increases in S. Typhi-specific LPMC CD103+ CD4+TRM (IFNγ and IL-17A) and CD103- CD4+TRM (IL-2 and IL-17A) responses following Ty21a-immunization. Further, differences in S. Typhi-specific responses between these two CD4+TRM subsets were observed following multifunctional analysis. In addition, we determined the effect of Ty21a-immunization on IEL and observed significant changes in the frequencies of IEL CD103+ (decrease) and CD103- CD4+TRM (increase) following immunization. Finally, we observed that IEL CD103- CD4+TRM, but not CD103+ CD4+TRM, produced increased cytokines (IFNγ, TNFα and IL-17A) to S. Typhi-specific stimulation following Ty21a-immunization.

Conclusions: Oral Ty21a-immunization elicits distinct compartment specific immune responses in CD4+TRM (CD103+ and CD103-) subsets. This study provides novel insights in the generation of local vaccine-specific responses. Trial registration This study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifier NCT03970304, Registered 29 May 2019-Retrospectively registered, http://www.ClinicalTrials.gov/NCT03970304).

Keywords: IEL; Oral vaccine; Terminal ileum LPMC; Tissue resident CD4+ T cells; Ty21a.

Conflict of interest statement

The authors declared no conflict of interest.

Figures

Fig. 1
Fig. 1
Gating Strategy and cell subset frequencies of terminal ileum tissue-resident memory CD4+ T (TRM) cells. Terminal ileum LPMC CD4+ tissue resident T memory cell (TRM) subsets in representative volunteers were detected in a Unvaccinated and Ty21a-vaccinated participants by expression of CD69 and CD103 markers following the gating strategy shown in the figure. b Frequencies of CD4+ CD103+ TRM and CD4+ CD103− TRM subsets were measured and compared between TI LPMC obtained from Ty21a-vaccinated (n = 18; red symbols) and unvaccinated volunteers (n = 18; black symbols) with significant differences (*p < 0.05) and a trend is indicated by its p-value. Horizontal bars represent median values
Fig. 2
Fig. 2
Effect of oral Ty21a-immunization on ex-vivo terminal ileum LPMC CD4+CD103+ and CD4+CD103− TRM. Ex-vivo unstimulated CD4+CD103+ and CD4+CD103− TRM were cultured overnight and their levels of spontaneous cytokine (IFNγ, IL-17A, IL-2 and TNFα) production determined by flow cytometry. Using the FCOM function of Winlist, CD4+CD103+ and CD8+CD103− TRM responses were stratified into single-positive cells (S) and multifunctional cells (MF). Comparison of TI LPMC CD4+ CD103+ and CD4+ CD103− TRM responses in a INFγ+; b IL-17A+; c IL-2+, and d TNFα+ S and MF in Ty21a-vaccinated (n = 18; red symbols) and unvaccinated volunteers (n = 18; black symbols) with significant differences shown (*p < 0.05; **p < 0.005; ***p < 0.0005). Black lines: differences between Ty21a vaccinated and unvaccinated volunteers. Green lines: differences between CD4+CD103+ and CD4+CD103− TRM cell responses. Trends are represented by their p-values. Horizontal bars (black and red) represent median values
Fig. 3
Fig. 3
S. Typhi-specific responses of terminal ileum LPMC CD4+CD103+ and CD8+CD103− TRM subsets in healthy individuals following oral Ty21a-immunization. The net percentages of S. Typhi-specific responses (IFNγ, IL-17A, IL-2, and TNFα) elicited by S. Typhi-infected autologous targets in a CD4+CD103+ and b CD4+CD103− TRM subsets were compared between Ty21a-vaccinated (n = 18; red symbols) and unvaccinated volunteers (n = 18; black symbols) with significant differences (*p < 0.05; **p < 0.005) indicated. Horizontal bars (black and red) represent median values
Fig. 4
Fig. 4
Effect of oral Ty21a immunization on terminal ileum multifunctional and single cytokine-expressing S. Typhi-specific CD4+CD103+ and CD4+CD103− TRM cell subsets. Net S. Typhi-specific CD4+ TRM subsets responses elicited by S. Typhi-infected autologous targets were calculated using the FCOM function of Winlist and stratified into multifunctional cells (MF) and single-positive cells (S). Comparison of TI LPMC CD4+CD103+ and CD4+CD103− TRMS. Typhi-specific a INFγ+; b IL-17A+; c IL-2+, and d TNFα+ MF and S in Ty21a-vaccinated (n = 18; red symbols) and unvaccinated volunteers (n = 18; black symbols). Significant differences are shown (*p < 0.05). Black lines: differences between Ty21a vaccinated and unvaccinated volunteers. Green lines: differences between CD4+CD103+ and CD4+CD103− TRM responses. Trends are represented by their p-values. Horizontal bars (black and red) represent median values
Fig. 5
Fig. 5
Multifunctional S. Typhi-specific responses to a Ty21a homogenate antigenic preparation by terminal ileum LPMC CD4+CD103+ and CD4+CD103− TRM subsets in healthy adults following oral Ty21a immunization. Terminal ileum LPMC CD4+CD103+ and CD4+CD103− TRM were stimulated with Ty21a homogenate antigen (10 μg/mL) as described in Materials and Methods. Net Ty21a homogenate (media subtracted) S. Typhi-specific CD4+ TRM subsets responses were calculated using the FCOM function of Winlist and stratified into multifunctional cells (MF) and single-positive cells (S). Comparison of TI LPMC CD4+CD103+ and CD4+CD103− TRM Ty21a homogenate mediated S. Typhi-specific a INFγ+; b IL-17A+; c IL-2+, and d TNFα+ MF and S responses in Ty21a-vaccinated (n = 8; red symbols) and unvaccinated volunteers (n = 8; black symbols). Significant differences are shown (*p < 0.05; **p < 0.005). Trends are represented by their p-values. Horizontal bars (black and red) represent median values
Fig. 6
Fig. 6
Gating Strategy for identifying terminal ileum intraepithelial T lymphocytes (IEL)-CD4+ tissue-resident T memory cell subsets (TRM) and impact of oral Ty21a-immunization on IEL CD4+ TRM subsets frequencies. Terminal ileum intraepithelial lymphocytes (IEL) were isolated and IEL CD4+ TRM studied in Ty21a vaccinated, and unvaccinated individuals using a combination of CD69 and CD103 markers. a Representative gating strategies for a Ty21a vaccinated and an unvaccinated participant are shown. b The frequencies of terminal ileum IEL CD4+ T and CD8+ T cells were determined and compared between TI IEL obtained from Ty21a-vaccinated (n = 17; red symbols) and unvaccinated volunteers (n = 17; black symbols). c The frequencies of terminal ileum IEL CD4+CD103+ and CD4+CD103− TRM cells were determined and compared between TI IEL obtained from Ty21a-vaccinated (n = 17; red symbols) and unvaccinated volunteers (n = 17; black symbols). Significant differences are shown (*p < 0.05; **p < 0.005; ***p < 0.0005). Horizontal bars represent median values
Fig. 7
Fig. 7
Effect of oral Ty21a immunization on ex-vivo terminal ileum IEL CD4+CD103+ and CD8+CD103− TRM. Ex-vivo unstimulated IEL CD4+CD103+ and CD4+CD103− TRM were cultured overnight and their spontaneous cytokine (IFNγ, IL-17A, IL-2 and TNFα) production were measured using flow cytometry. Using the FCOM function of WinList, IEL CD4+CD103+ and CD4+CD103− TRM responses were stratified into single-positive cells (S) and multifunctional cells (MF). Comparisons of TI IEL CD4+CD103+ and CD4+CD103− TRM responses in a INFγ+; b IL-17A+; c IL-2+, and d TNFα+ S and MF in Ty21a-vaccinated (n = 17; red symbols) and unvaccinated volunteers (n = 17; black symbols) with significant differences shown (*p < 0.05; **p < 0.005; ***p < 0.0005). Black lines: significant differences between Ty21a vaccinated and unvaccinated volunteers. Horizontal bars (black and red) represent median values
Fig. 8
Fig. 8
Effect of oral Ty21a immunization on terminal ileum multifunctional and single cytokine expressing S. Typhi-specific IEL CD4+CD103+ and CD4+CD103− TRM cell subsets. Net S. Typhi-specific IEL CD4+ TRM subsets responses elicited by S. Typhi-infected autologous targets were calculated using the FCOM function of WinList and stratified into multifunctional cells (MF) and single-positive cells (S). Comparison of TI IEL CD4+CD103+ and CD4+CD103− TRMS. Typhi-specific a INFγ+; b IL-17A+; c IL-2+, and d TNFα+ MF and S in Ty21a-vaccinated (n = 7; red symbols) and unvaccinated volunteers (n = 6; black symbols). Significant differences are shown (*p < 0.05). Horizontal bars (black and red) represent median values

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