Varicella zoster-specific CD4+Foxp3+ T cells accumulate after cutaneous antigen challenge in humans

• Published in: The Journal of immunology (1950) Vol. 190; no. 3; pp. 977 - 986
• Main Authors: Vukmanovic-Stejic, Milica, Sandhu, Daisy, Sobande, Toni O, Agius, Elaine, Lacy, Katie E, Riddell, Natalie, Montez, Sandra, Dintwe, One B, Scriba, Thomas J, Breuer, Judith, Nikolich-Zugich, Janko, Ogg, Graham, Rustin, Malcolm H A, Akbar, Arne N
• Format: Journal Article
• Language: English
• Published: United States 01.02.2013
• Subjects: Adult; Aged; Aged, 80 and over; Aging - immunology; Antigens, CD - analysis; Antigens, Viral - administration & dosage; Antigens, Viral - immunology; CD4-Positive T-Lymphocytes - chemistry; CD4-Positive T-Lymphocytes - immunology; Female; Forkhead Transcription Factors - analysis; Herpesvirus 3, Human - immunology; Humans; Hypersensitivity, Delayed - immunology; Immediate-Early Proteins - administration & dosage; Immediate-Early Proteins - immunology; Immunodominant Epitopes - immunology; Immunologic Memory; Injections, Intradermal; Intradermal Tests; Ki-67 Antigen - analysis; Lymphocyte Activation; Male; Middle Aged; Skin - immunology; T-Cell Antigen Receptor Specificity; T-Lymphocyte Subsets - chemistry; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - immunology; Tuberculin Test; Varicella-zoster virus; Viral Envelope Proteins - administration & dosage; Viral Envelope Proteins - immunology; Young Adult
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1201331

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.