Systemic and Terminal Ileum Mucosal Immunity Elicited by Oral Immunization With the Ty21a Typhoid Vaccine in Humans

Jayaum S Booth; Seema A Patil; Leyla Ghazi; Robin Barnes; Claire M Fraser; Alessio Fasano; Bruce D Greenwald; Marcelo B Sztein

doi:10.1016/j.jcmgh.2017.08.002

Systemic and Terminal Ileum Mucosal Immunity Elicited by Oral Immunization With the Ty21a Typhoid Vaccine in Humans

Cell Mol Gastroenterol Hepatol. 2017 Aug 16;4(3):419-437. doi: 10.1016/j.jcmgh.2017.08.002. eCollection 2017 Nov.

Authors

Jayaum S Booth^{1

2}, Seema A Patil^{3

4}, Leyla Ghazi^{3

4}, Robin Barnes¹, Claire M Fraser^{3

5}, Alessio Fasano⁶, Bruce D Greenwald^{3

4}, Marcelo B Sztein^{1

2

3}

Affiliations

¹ Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland.
² Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland.
³ Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
⁴ Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland.
⁵ Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland.
⁶ Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, Massachusetts.

Abstract

Background & aims: Systemic cellular immunity elicited by the Ty21a oral typhoid vaccine has been extensively characterized. However, very limited data are available in humans regarding mucosal immunity at the site of infection (terminal ileum [TI]). Here we investigated the host immunity elicited by Ty21a immunization on terminal ileum-lamina propria mononuclear cells (LPMC) and peripheral blood in volunteers undergoing routine colonoscopy.

Methods: We characterized LPMC-T memory (T_M) subsets and assessed Salmonella enterica serovar Typhi (S Typhi)-specific responses by multichromatic flow cytometry.

Results: No differences were observed in cell yields and phenotypes in LPMC CD8⁺-T_M subsets following Ty21a immunization. However, Ty21a immunization elicited LPMC CD8⁺ T cells exhibiting significant S Typhi-specific responses (interferon-γ, tumor necrosis factor-α, interleukin-17A, and/or CD107a) in all major T_M subsets (T-effector/memory [T_EM], T-central/memory, and T_EM-CD45RA⁺), although each T_M subset exhibited unique characteristics. We also investigated whether Ty21a immunization elicited S Typhi-specific multifunctional effectors in LPMC CD8⁺ T_EM. We observed that LPMC CD8⁺ T_EM responses were mostly multifunctional, except for those cells exhibiting the characteristics associated with cytotoxic responses. Finally, we compared mucosal with systemic responses and made the important observation that LPMC CD8⁺S Typhi-specific responses were unique and distinct from their systemic counterparts.

Conclusions: This study provides the first demonstration of S Typhi-specific responses in the human terminal ileum mucosa and provides novel insights into the generation of mucosal immune responses following oral Ty21a immunization.

Keywords: CD8+-T Memory Cells; CMI, cell-mediated immune responses; EBV-B, Epstein-Barr virus–transformed lymphoblastoid B cells; IFN, interferon; IL, interleukin; LPMC, lamina propria mononuclear cells; Lamina Propria Mononuclear Cells; MF, multifunctional; MIP, macrophage inflammatory protein; Multifunctional T Cells; PBMC, peripheral blood mononuclear cells; S, S Typhi–specific single producing cells; TCM, T-central/memory (CD62L+CD45RA-); TEM, T-effector/memory (CD62L-CD45RA-); TEMRA, TEM-CD45RA+ (CD62L-CD45RA+); TI, terminal ileum; TM, CD8+ T memory; TNF, tumor necrosis factor; Typhoid; Vaccines; wt, wild-type.

Abstract

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