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

Booth, Jayaum S.; Goldberg, Eric; Patil, Seema; Barnes, Robin S.; Greenwald, Bruce D.; Sztein, Marcelo B.

doi:10.1093/intimm/dxy070

Cited by 11 publications

(24 citation statements)

References 49 publications

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“…Here, we showed that the IFNγ and IL-17A are primarily produced by CD4+T RM (a subset of CD4+ T EM ) in significantly higher levels in the terminal ileum mucosa following Ty21a immunization. In addition, we observed that CD103+ CD4+T RM produced cytokines as monofunctional cells whereas CD103− CD4+T RM cells produced mostly multifunctional cytokines, similar to our observations in LPMC CD4+T EM [50]. These results suggest that examination of heterogeneous CD4+ T populations may mask the 'true' impact of oral Ty21a immunization due to the 'averaging effect' inherent to the analyses of whole populations/subsets which are composed of responding and non-responding cells.…”

Section: Discussionsupporting

confidence: 87%

“…We have previously characterized S. Typhi-specific LPMC CD4+T EM cells and observed increasing trends in IFNγ and IL-17A production following Ty21a immunization [50]. Here, we showed that the IFNγ and IL-17A are primarily produced by CD4+T RM (a subset of CD4+ T EM ) in significantly higher levels in the terminal ileum mucosa following Ty21a immunization.…”

Section: Discussionmentioning

confidence: 57%

“…S1) as previously described [25,32]. Target cells were then infected with wt-S. Typhi strain ISP1820 at a MOI of 7:1 as previously described [35]. Infected target cells were then gamma-irradiated (6000 rad) before used for ex vivo LPMC and IEL stimulation.…”

Section: Target Cell Preparation and S Typhi Infectionmentioning

confidence: 99%

“…CD4+T M cells have been shown to respond to both autologous S. Typhi-infected and soluble antigens (e.g., Ty21a homogenate) [35]. Thus, we stimulated both CD4+T RM subsets with Ty21a homogenate (10 μg/ mL) and determined their net responses (% of Ty21a homogenate responses-% of unstimulated (cell alone) responses) in a subgroup of Ty21a vaccinated (n = 8) and unvaccinated (n = 8) volunteers.…”

Section: Lpmc-cd4+t Rm Subsets Exhibited Distinct Responses To Stimulmentioning

confidence: 99%

“…Furthermore, CD4+T EM and T EMRA subsets responses displayed increases in S. Typhi-specific multifunctional (MF) cells post-vaccination mainly producing IFN-γ and/or TNF-α, while IL-2, MIP-1β, IL-17A and CD107a expression (a marker associated with cytotoxicity) were produced in a small proportion of MF cells [33]. Recently, we reported that oral Ty21a-immunization elicits significant TI lamina propria mononuclear cells (LPMC) S. Typhi-specific CD8+ T M [34], CD8+T RM [16], and CD4+T M [35] responses with distinct effector functions. However, it is unknown whether LPMC CD4+T RM are elicited following oral Ty21a immunization.…”

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confidence: 99%

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

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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 (T RM ) cells provide immediate adaptive effector immune responsiveness at the infection site. However, the mechanism(s) by which S. Typhi induces T RM in the intestinal mucosa are unknown. Here, we focus on the induction of S. Typhi-specific CD4+T RM 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+T RM immune responses were determined using either S. Typhi-infected or noninfected 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+T RM were significant decreased, both CD103+ and CD103− CD4+T RM 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+T RM (IFNγ and IL-17A) and CD103− CD4+T RM (IL-2 and IL-17A) responses following Ty21a-immunization. Further, differences in S. Typhi-specific responses between these two CD4+T RM 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+T RM (increase) following immunization. Finally, we observed that IEL CD103− CD4+T RM , but not CD103+ CD4+T RM , produced increased cytokines (IFNγ, TNFα and IL-17A) to S. Typhi-specific stimulation following Ty21a-immunization. © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article' Conclusions: Oral Ty21a-immunization elicits distinct compartment sp...

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 57%

Section: Target Cell Preparation and S Typhi Infectionmentioning

confidence: 99%

Section: Lpmc-cd4+t Rm Subsets Exhibited Distinct Responses To Stimulmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2020

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

et al. 2020

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Objective. There are no vaccines for most of the major invasive Salmonella strains causing severe infection in humans. We evaluated the specificity of adaptive T memory cell responses generated after Salmonella Typhi exposure in humans against other major invasive Salmonella strains sharing capacity for dissemination. Methods. T memory cells from eleven volunteers who underwent controlled oral challenge with wt S. 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 S. Typhi, Salmonella Paratyphi A (PA), S. Paratyphi B (PB) or an invasive nontyphoidal Salmonella strain of the S. Typhimurium serovar (iNTSTy). Results. Blood T-cell effector memory (T EM) responses after exposure to S. Typhi in humans evolve late, peaking weeks after infection in most volunteers. Induced multifunctional CD4 + Th1 and CD8 + T EM cells elicited after S. Typhi challenge were cross-reactive with PA, PB and iNTSTy. The magnitude of multifunctional CD4 + T EM cell responses to S. Typhi correlated with induction of cross-reactive multifunctional CD8 + T EM cells against PA, PB and iNTSTy. Highly multifunctional subsets and T central memory and T effector memory cells that re-express CD45 (T EMRA) demonstrated less heterologous T-cell cross-reactivity, and multifunctional Th17 elicited after S. Typhi challenge was not crossreactive against other invasive Salmonella. Conclusion. Gaps in crossreactive immune effector functions in human T-cell memory compartments were highly dependent on invasive Salmonella strain, underscoring the importance of strain-dependent vaccination in the design of T-cell-based vaccines for invasive Salmonella.

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

Abstract: Mucosal CD4+ T memory responses after typhoid immunization

Cited by 11 publications

References 49 publications

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

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

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

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