title: Human antigen-specific CD4⁺ CD25⁺ CD134⁺ CD39⁺ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses.
abstract: Human Ag-specific CD4(+) T cells can be detected by their dual expression of CD134 (OX40) and CD25 after a 44 hours stimulation with cognate Ag. We show that surface expression of CD39 on Ag-specific cells consistently identifies a substantial population of CD4(+) CD25(+) CD134(+) CD39(+) T cells that have a Treg-cell-like phenotype and mostly originate from bulk memory CD4(+) CD45RO(+) CD127(low) CD25(high) CD39(+) Treg cells. Viable, Ag-specific CD25(+) CD134(+) CD39(+) T cells could be expanded in vitro as cell lines and clones, and retained high Forkhead Box Protein 3, CTLA-4 and CD39 expression, suppressive activity and Ag specificity. We also utilised this combination of cell surface markers to measure HIV-Gag responses in HIV(+) patients before and after anti-retroviral therapy (ART). Interestingly, we found that the percentage of CD39(-) cells within baseline CD4(+) T-cell responses to HIV-Gag was negatively correlated with HIV viral load pre-ART and positively correlated with CD4(+) T-cell recovery over 96 weeks of ART. Collectively, our data show that Ag-specific CD4(+) CD25(+) CD134(+) CD39(+) T cells are highly enriched for Treg cells, form a large component of recall responses and maintain a Treg-cell-like phenotype upon in vitro expansion. Identification and isolation of these cells enables the role of Treg cells in memory responses to be further defined and provides a development pathway for novel therapeutics.
authors.affiliation: The Kirby Institute, University of New South Wales, Sydney, NSW, Australia; St Vincent's Centre for Applied Medical Research, Sydney, NSW, Australia.
authors.forename: Nabila
authors.initials: N
authors.lastname: Seddiki
authors.forename: Laura
authors.initials: L
authors.lastname: Cook
authors.forename: Denise C
authors.initials: DC
authors.lastname: Hsu
authors.forename: Chansavath
authors.initials: C
authors.lastname: Phetsouphanh
authors.forename: Kai
authors.initials: K
authors.lastname: Brown
authors.forename: Yin
authors.initials: Y
authors.lastname: Xu
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kerr
authors.forename: David A
authors.initials: DA
authors.lastname: Cooper
authors.forename: C Mee Ling
authors.initials: CM
authors.lastname: Munier
authors.forename: Sarah
authors.initials: S
authors.lastname: Pett
authors.forename: Jintanat
authors.initials: J
authors.lastname: Ananworanich
authors.forename: John
authors.initials: J
authors.lastname: Zaunders
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kelleher
mesh_terms: D015703:Antigens, CD / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology*; D001081:Apyrase / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D016655:HIV Core Protein p24 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008297:Male; D053262:Receptors, OX40 / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D019562:Viral Load / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000956:Antigens, Viral; D015704:CD4 Antigens; D016655:HIV Core Protein p24; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D053262:Receptors, OX40; C505716:TNFRSF4 protein, human; C514799:p24 protein, Human Immunodeficiency Virus Type 1; D001081:Apyrase; C067869:CD39 antigen
keywords: Antigen-specific T cells; CD134; CD25; CD39; FOXP3; OX40; Treg cell