Transcriptional profiles reveal a stepwise developmental program of memory CD8+ T cell differentiation

Rahul Roychoudhuri, Francois Lefebvre, Mitsuo Honda, Li Pan, Yun Ji, Christopher A. Klebanoff, Carmen N. Nichols, Slim Fourati, Ahmed N. Hegazy, Jean Philippe Goulet, Luca Gattinoni, Gary J. Nabel, Michel Gilliet, Mark Cameron, Nicholas P. Restifo, Rafick P. Sékaly, Lukas Flatz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

The generation of CD8+ T-cell memory is a major aim of vaccination. While distinct subsets of CD8+ T-cells are generated following immunization that differ in their ability to confer long-term immunity against infection, the transcriptional profiles of these subsets within endogenous vaccine-induced CD8+ T cell responses have not been resolved. Here, we measure global transcriptional profiles of endogenous effector (TEFF), effector memory (TEM) and central memory (TCM) CD8+ T-cells arising from immunization with three distinct prime-boost vaccine regimens. While a proportion of transcripts were uniquely regulated within distinct CD8+ T cell populations, we observed progressive up- or down-regulation in the expression of a majority of differentially expressed transcripts when subsets were compared in the order TN>TCM>TEM>TEFF. Strikingly, when we compared global differences in gene expression between TN, TCM, TEM and TEFF cells with known transcriptional changes that result when CD8+ T cells repetitively encounter antigen, our analysis overwhelmingly favored a model whereby cumulative antigen stimulation drives differentiation specifically from TN>TCM>TEM>TEFF and this was common to all vaccines tested. These findings provide insight into the molecular basis of immunological memory and identify potential biomarkers for characterization of vaccine-induced responses and prediction of vaccine efficacy.

Original languageEnglish (US)
Pages (from-to)914-923
Number of pages10
JournalVaccine
Volume33
Issue number7
DOIs
StatePublished - Feb 11 2015

Funding

We thank S. Perfetto, E. Lugli, M. Vernez, A. Bergthaler and G. Fabozzi, D.C. Macallan and G.E. Griffin for helpful insights and discussion. We also thank R. Nguyen and D. Ambrozak for their expertise with FACS sorting. This research was supported by the Intramural Research Programs of the US National Institutes of Health , National Institute of Allergy and Infectious Diseases and National Cancer Institute . L.F. is supported by the Stiftung Propter Homines, Vaduz, Principality of Liechtenstein, the Fondation Leenaards and the Medic Foundation. A.N.H. was supported by a European Molecular Biology Organization (EMBO) long-term fellowship (ALTF 116-2012) and a Marie Curie fellowship (FP7-PEOPLE-2012-IEF, Proposal 330621). R.R. is supported by a Fellowship from the Wellcome Trust.

Keywords

  • Adenovirus vector
  • CD8
  • LCMV vector
  • Memory T cells
  • Prime-boost vaccination
  • T cell memory

ASJC Scopus subject areas

  • Molecular Medicine
  • General Immunology and Microbiology
  • General Veterinary
  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

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