title: Transcriptional profiles reveal a stepwise developmental program of memory CD8(+) T cell differentiation.
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.
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: roychoudhuri@mail.nih.gov.
authors.forename: Rahul
authors.initials: R
authors.lastname: Roychoudhuri
authors.affiliation: Vaccine and Gene Therapy Institute, Port St. Lucie, FL 34987, USA.
authors.forename: Francois
authors.initials: F
authors.lastname: Lefebvre
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Honda
authors.affiliation: Vaccine and Gene Therapy Institute, Port St. Lucie, FL 34987, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Pan
authors.affiliation: National Cancer Institute (NCI), National Institutes of Bethesda, Bethesda, MD 20892, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ji
authors.affiliation: National Cancer Institute (NCI), National Institutes of Bethesda, Bethesda, MD 20892, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.affiliation: Vaccine and Gene Therapy Institute, Port St. Lucie, FL 34987, USA.
authors.forename: Carmen N
authors.initials: CN
authors.lastname: Nichols
authors.affiliation: Vaccine and Gene Therapy Institute, Port St. Lucie, FL 34987, USA.
authors.forename: Slim
authors.initials: S
authors.lastname: Fourati
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Ahmed N
authors.initials: AN
authors.lastname: Hegazy
authors.affiliation: Vaccine and Gene Therapy Institute, Port St. Lucie, FL 34987, USA.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Goulet
authors.affiliation: National Cancer Institute (NCI), National Institutes of Bethesda, Bethesda, MD 20892, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
authors.affiliation: Department of Dermatology, University Hospital CHUV, 1011 Lausanne, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Gilliet
authors.affiliation: Vaccine and Gene Therapy Institute, Port St. Lucie, FL 34987, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Cameron
authors.affiliation: National Cancer Institute (NCI), National Institutes of Bethesda, Bethesda, MD 20892, USA.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.affiliation: Vaccine and Gene Therapy Institute, Port St. Lucie, FL 34987, USA. Electronic address: rpsekaly@vgtifl.org.
authors.forename: Rafick P
authors.initials: RP
authors.lastname: Sékaly
authors.affiliation: Department of Dermatology, University Hospital CHUV, 1011 Lausanne, Switzerland; Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland. Electronic address: lukas.flatz@gmail.com.
authors.forename: Lukas
authors.initials: L
authors.lastname: Flatz
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D007156:Immunologic Memory / Q000276:immunology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis
keywords: Adenovirus vector; CD8; LCMV vector; Memory T cells; Prime-boost vaccination; T cell memory