title: Compartmentalization of Total and Virus-Specific Tissue-Resident Memory CD8+ T Cells in Human Lymphoid Organs.
abstract: Disruption of T cell memory during severe immune suppression results in reactivation of chronic viral infections, such as Epstein Barr virus (EBV) and Cytomegalovirus (CMV). How different subsets of memory T cells contribute to the protective immunity against these viruses remains poorly defined. In this study we examined the compartmentalization of virus-specific, tissue resident memory CD8+ T cells in human lymphoid organs. This revealed two distinct populations of memory CD8+ T cells, that were CD69+CD103+ and CD69+CD103-, and were retained within the spleen and tonsils in the absence of recent T cell stimulation. These two types of memory cells were distinct not only in their phenotype and transcriptional profile, but also in their anatomical localization within tonsils and spleen. The EBV-specific, but not CMV-specific, CD8+ memory T cells preferentially accumulated in the tonsils and acquired a phenotype that ensured their retention at the epithelial sites where EBV replicates. In vitro studies revealed that the cytokine IL-15 can potentiate the retention of circulating effector memory CD8+ T cells by down-regulating the expression of sphingosine-1-phosphate receptor, required for T cell exit from tissues, and its transcriptional activator, Kruppel-like factor 2 (KLF2). Within the tonsils the expression of IL-15 was detected in regions where CD8+ T cells localized, further supporting a role for this cytokine in T cell retention. Together this study provides evidence for the compartmentalization of distinct types of resident memory T cells that could contribute to the long-term protection against persisting viral infections.
authors.affiliation: Centenary Institute, The University of Sydney, Newtown, New South Wales, Australia.
authors.forename: Heng Giap
authors.initials: HG
authors.lastname: Woon
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Asolina
authors.identifier: 0000-0002-2646-5362
authors.initials: A
authors.lastname: Braun
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Jane
authors.initials: J
authors.lastname: Li
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Corey
authors.initials: C
authors.lastname: Smith
authors.affiliation: Centenary Institute, The University of Sydney, Newtown, New South Wales, Australia.
authors.forename: Jarem
authors.initials: J
authors.lastname: Edwards
authors.affiliation: Centenary Institute, The University of Sydney, Newtown, New South Wales, Australia.
authors.forename: Frederic
authors.initials: F
authors.lastname: Sierro
authors.affiliation: Centenary Institute, The University of Sydney, Newtown, New South Wales, Australia.|Discipline of Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, Newtown, New South Wales, Australia.
authors.forename: Carl G
authors.initials: CG
authors.lastname: Feng
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Khanna
authors.affiliation: Chris O'Brien Lifehouse Cancer Centre, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales, Australia.|Sydney Medical School, The University of Sydney, Newtown, New South Wales, Australia.
authors.forename: Michael
authors.identifier: 0000-0003-3028-2486
authors.initials: M
authors.lastname: Elliot
authors.affiliation: School of Cancer Sciences and MRC Centre for Immune Regulation, University of Birmingham, Edgbaston, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bell
authors.affiliation: School of Cancer Sciences and MRC Centre for Immune Regulation, University of Birmingham, Edgbaston, United Kingdom.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hislop
authors.affiliation: Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.|St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.affiliation: School of Cancer Sciences and MRC Centre for Immune Regulation, University of Birmingham, Edgbaston, United Kingdom.
authors.forename: Alan B
authors.initials: AB
authors.lastname: Rickinson
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gebhardt
authors.affiliation: Centenary Institute, The University of Sydney, Newtown, New South Wales, Australia.|Sydney Medical School, The University of Sydney, Newtown, New South Wales, Australia.
authors.forename: Warwick J
authors.initials: WJ
authors.lastname: Britton
authors.affiliation: Centenary Institute, The University of Sydney, Newtown, New South Wales, Australia.|Sydney Medical School, The University of Sydney, Newtown, New South Wales, Australia.
authors.forename: Umaimainthan
authors.identifier: 0000-0002-1113-3306
authors.initials: U
authors.lastname: Palendira
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000473:pathology; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000473:pathology; D005260:Female; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D019409:Interleukin-15 / Q000276:immunology; D051741:Kruppel-Like Transcription Factors / Q000276:immunology; D008297:Male; D009928:Organ Specificity / Q000276:immunology
chemical_list: D015703:Antigens, CD; C569274:IL15 protein, human; D019409:Interleukin-15; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors