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Front. Immunol. | doi: 10.3389/fimmu.2019.00257

Age-Associated Heterogeneity of Ty21a-Induced T Cell Responses to HLA-E Restricted Salmonella Typhi Antigen Presentation

 Mark E. Rudolph1, 2*, Monica A. McArthur1, 3, Laurence S. Magder4, Robin S. Barnes1, Wilbur H. Chen1, 5 and Marcelo B. Sztein1, 2, 3, 5*
  • 1Center for Vaccine Development and Global Health, University of Maryland, Baltimore, United States
  • 2Department of Microbiology and Immunology, School of Medicine, University of Maryland, United States
  • 3Department of Pediatrics, School of Medicine, University of Maryland, United States
  • 4Department of Epidemiology and Public Health, School of Medicine, University of Maryland, United States
  • 5School of Medicine, University of Maryland, United States

Human-restricted Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever—a life-threatening disease of great global health significance, particularly in the developing world. Ty21a is an oral live-attenuated vaccine that protects against the development of typhoid disease in part by inducing robust T cell responses, among which multifunctional CD8+ cytotoxic T lymphocytes (CTL) play an important role. Following Ty21a vaccination, a significant component of adult CTL have shown to be targeted to S. Typhi antigen presented by the conserved major histocompatibility complex (MHC) class Ib molecule, human leukocyte antigen-E (HLA-E). S. Typhi challenge studies have shown that baseline, multifunctional HLA-E responsive T cells are associated with protection from, and delayed onset of, typhoid disease. However, despite the overwhelming burden of typhoid fever in school-aged children, and due to limited availability of pediatric samples, incomplete information is available regarding these important HLA-E-restricted responses in children, even though studies have shown that younger children may be less likely to develop protective cell mediated immune (CMI) responses than adults following vaccination. To address this gap, we have studied this phenomenon in depth by using mass cytometry to analyze pediatric and adult T cell responses to HLA-E-restricted S. Typhi antigen presentation, before and after Ty21a vaccination. Herein, we show variable responses in all age strata following vaccination among T effector memory (TEM) and T effector memory CD45RA+ (TEMRA) cells based on conventional gating analysis. However, by utilizing the dimensionality reduction tool tSNE (t-distributed Stochastic Neighbor Embedding), we are able to identify diverse, highly multifunctional gut-homing- TEM and TEMRA clusters of cells which are more abundant in adult and older pediatric participants than in younger children. These findings highlight a potential age-associated maturation of otherwise conserved HLA-E restricted T cell responses. Such insights, coupled with the marked importance of multifunctional T cell responses to combat infection, may better inform future pediatric vaccination strategies against S. Typhi and other infectious diseases.

Keywords: T cell response, dimensionality reduction, Ty21a, multifunctionality, Pediatric Immunology, Salmonella typhi, HLA-E Restricted Responses, typhoid

Received: 20 Jul 2018; Accepted: 29 Jan 2019.

Edited by:

Fabio Bagnoli, GlaxoSmithKline (Italy), Italy

Reviewed by:

Richard A. Strugnell, The University of Melbourne, Australia
Simone Joosten, Leiden University Medical Center, Netherlands  

Copyright: © 2019 Rudolph, McArthur, Magder, Barnes, Chen and Sztein. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Mr. Mark E. Rudolph, University of Maryland, Baltimore, Center for Vaccine Development and Global Health, Baltimore, United States,
Dr. Marcelo B. Sztein, University of Maryland, Baltimore, Center for Vaccine Development and Global Health, Baltimore, United States,