title: Varicella zoster-specific CD4+Foxp3+ T cells accumulate after cutaneous antigen challenge in humans.
abstract: We investigated the relationship between varicella zoster virus (VZV)-specific memory CD4(+) T cells and CD4(+)Foxp3(+) regulatory T cells (Tregs) that accumulate after intradermal challenge with a VZV skin test Ag. VZV-specific CD4(+) T cells were identified with a MHC class II tetramer or by intracellular staining for either IFN-γ or IL-2 after Ag rechallenge in vitro. VZV-specific T cells, mainly of a central memory (CD45RA(-)CD27(+)) phenotype, accumulate at the site of skin challenge compared with the blood of the same individuals. This resulted in part from local proliferation because >50% of tetramer defined Ag-specific CD4(+) T cells in the skin expressed the cell cycle marker Ki67. CD4(+)Foxp3(+) T cells had the characteristic phenotype of Tregs, namely CD25(hi)CD127(lo)CD39(hi) in both unchallenged and VZV challenged skin and did not secrete IFN-γ or IL-2 after antigenic restimulation. The CD4(+)Foxp3(+) T cells from unchallenged skin had suppressive activity, because their removal led to an increase in cytokine secretion after activation. After VZV Ag injection, Foxp3(+)CD25(hi)CD127(lo)CD39(hi) T cells were also found within the VZV tetramer population. Their suppressive activity could not be directly assessed by CD25 depletion because activated T cells in the skin were also CD25(+). Nevertheless, there was an inverse correlation between decreased VZV skin responses and proportion of CD4(+)Foxp3(+) T cells present, indicating indirectly their inhibitory activity in vivo. These results suggest a linkage between the expansion of Ag-specific CD4(+) T cells and CD4(+) Tregs that may provide controlled responsiveness during Ag-specific stimulation in tissues.
authors.affiliation: Division of Infection and Immunity, University College London, London W1T 4JF, United Kingdom.
authors.forename: Milica
authors.initials: M
authors.lastname: Vukmanovic-Stejic
authors.forename: Daisy
authors.initials: D
authors.lastname: Sandhu
authors.forename: Toni O
authors.initials: TO
authors.lastname: Sobande
authors.forename: Elaine
authors.initials: E
authors.lastname: Agius
authors.forename: Katie E
authors.initials: KE
authors.lastname: Lacy
authors.forename: Natalie
authors.initials: N
authors.lastname: Riddell
authors.forename: Sandra
authors.initials: S
authors.lastname: Montez
authors.forename: One B
authors.initials: OB
authors.lastname: Dintwe
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Scriba
authors.forename: Judith
authors.initials: J
authors.lastname: Breuer
authors.forename: Janko
authors.initials: J
authors.lastname: Nikolich-Zugich
authors.forename: Graham
authors.initials: G
authors.lastname: Ogg
authors.forename: Malcolm H A
authors.initials: MH
authors.lastname: Rustin
authors.forename: Arne N
authors.initials: AN
authors.lastname: Akbar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology; D015703:Antigens, CD / Q000032:analysis; D000956:Antigens, Viral / Q000008:administration & dosage / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D014645:Herpesvirus 3, Human / Q000276:immunology*; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D017874:Immediate-Early Proteins / Q000008:administration & dosage / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000276:immunology; D007156:Immunologic Memory; D007271:Injections, Intradermal; D007428:Intradermal Tests; D019394:Ki-67 Antigen / Q000032:analysis; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D012867:Skin / Q000276:immunology*; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014374:Tuberculin Test; D014759:Viral Envelope Proteins / Q000008:administration & dosage / Q000276:immunology*; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D000956:Antigens, Viral; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D017874:Immediate-Early Proteins; D016056:Immunodominant Epitopes; D019394:Ki-67 Antigen; D014759:Viral Envelope Proteins; C074551:immediate early protein 63, Human herpesvirus 3