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VZV-specific CD4+ T cells were identified with a MHC class II tetramer or by intracellular staining for either IFN-\u03b3 or IL-2 after Ag rechallenge in vitro. VZV-specific T cells, mainly of a central memory (CD45RA\u2212CD27+) phenotype, accumulate at the site of skin challenge compared with the blood of the same individuals. This resulted in part from local proliferation because &amp;gt;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 CD25hiCD127loCD39hi in both unchallenged and VZV challenged skin and did not secrete IFN-\u03b3 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+CD25hiCD127loCD39hi 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.<\/jats:p>","DOI":"10.4049\/jimmunol.1201331","type":"journal-article","created":{"date-parts":[[2013,1,3]],"date-time":"2013-01-03T07:17:47Z","timestamp":1357197467000},"page":"977-986","source":"Crossref","is-referenced-by-count":58,"title":["Varicella Zoster\u2013Specific CD4+Foxp3+ T Cells Accumulate after Cutaneous Antigen Challenge in Humans"],"prefix":"10.1093","volume":"190","author":[{"given":"Milica","family":"Vukmanovic-Stejic","sequence":"first","affiliation":[{"name":"Division of Infection and Immunity, University College London , London W1T 4JF,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisy","family":"Sandhu","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, University College London , London W1T 4JF,","place":["United Kingdom"]},{"name":"Department of Dermatology, Royal Free Hospital , London NW3 2QG,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toni O","family":"Sobande","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, University College London , London W1T 4JF,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Agius","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, University College London , London W1T 4JF,","place":["United Kingdom"]},{"name":"Department of Dermatology, Royal Free Hospital , London NW3 2QG,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie E","family":"Lacy","sequence":"additional","affiliation":[{"name":"National Institute for Health Research Biomedical Research Centre at Guy\u2019s and St. Thomas\u2019s Hospitals and King\u2019s College London, St. John\u2019s Institute of Dermatology, Division of Genetics and Molecular Medicine, King\u2019s College London , London SE1 9RT,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Riddell","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, University College London , London W1T 4JF,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Montez","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, University College London , London W1T 4JF,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"One B","family":"Dintwe","sequence":"additional","affiliation":[{"name":"South African Tuberculosis Vaccine Initiative and School of Child and Adolescent Health, Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town, Rondebosch 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