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

Milica Vukmanovic-Stejic, Daisy Sandhu, Toni O. Sobande, Elaine Agius, Katie E. Lacy, Natalie Riddell, Sandra Montez, One B. Dintwe, Thomas J. Scriba, Judith Breuer, Janko Nikolich-Zugich, Graham Ogg, Malcolm H A Rustin, Arne N. Akbar

Research output: Contribution to journalArticle

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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-g or IL-2 after Ag rechallenge in vitro. VZV-specific T cells, mainly of a central memory (CD45RA2CD27+) 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 CD25hiCD127loCD39hi in both unchallenged and VZV challenged skin and did not secrete IFN-g 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 VZVAg 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+Foxp 3+ 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.

Original languageEnglish (US)
Pages (from-to)977-986
Number of pages10
JournalJournal of Immunology
Volume190
Issue number3
DOIs
StatePublished - Feb 1 2013

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Chickenpox
Herpes Zoster
Human Herpesvirus 3
T-Lymphocytes
Antigens
Skin
Interleukin-2
Phenotype
Regulatory T-Lymphocytes
Skin Tests
Cell Cycle
Staining and Labeling
Cytokines
Injections

ASJC Scopus subject areas

  • Immunology

Cite this

Vukmanovic-Stejic, M., Sandhu, D., Sobande, T. O., Agius, E., Lacy, K. E., Riddell, N., ... Akbar, A. N. (2013). Varicella zoster-specific CD4+Foxp3+ T cells accumulate after cutaneous antigen challenge in humans. Journal of Immunology, 190(3), 977-986. https://doi.org/10.4049/jimmunol.120133

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

In: Journal of Immunology, Vol. 190, No. 3, 01.02.2013, p. 977-986.

Research output: Contribution to journalArticle

Vukmanovic-Stejic, M, Sandhu, D, Sobande, TO, Agius, E, Lacy, KE, Riddell, N, Montez, S, Dintwe, OB, Scriba, TJ, Breuer, J, Nikolich-Zugich, J, Ogg, G, Rustin, MHA & Akbar, AN 2013, 'Varicella zoster-specific CD4+Foxp3+ T cells accumulate after cutaneous antigen challenge in humans', Journal of Immunology, vol. 190, no. 3, pp. 977-986. https://doi.org/10.4049/jimmunol.120133
Vukmanovic-Stejic M, Sandhu D, Sobande TO, Agius E, Lacy KE, Riddell N et al. Varicella zoster-specific CD4+Foxp3+ T cells accumulate after cutaneous antigen challenge in humans. Journal of Immunology. 2013 Feb 1;190(3):977-986. https://doi.org/10.4049/jimmunol.120133
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. / Varicella zoster-specific CD4+Foxp3+ T cells accumulate after cutaneous antigen challenge in humans. In: Journal of Immunology. 2013 ; Vol. 190, No. 3. pp. 977-986.
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