Journal
JOURNAL OF IMMUNOLOGY
Volume 190, Issue 3, Pages 977-986Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1201331
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Funding
- Medical Research Council
- British Biological and Biotechnological Science Council
- British Skin Foundation
- Dermatrust
- National Institutes of Health-Biotechnology and Biological Sciences Research Council [BB/H020519/1]
- BBSRC [BB/G530433/1, BB/H020519/1] Funding Source: UKRI
- MRC [MC_U137881017, G0700814, G0901102, G0701693, MC_UU_12010/5] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/G530433/1, BB/H020519/1] Funding Source: researchfish
- Medical Research Council [G1000800h, G0901102, MC_UU_12010/5, G0701693, MC_U137881017, G0700814] Funding Source: researchfish
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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-gamma 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 CD(25hi)CD12(lo)CD39(hi) in both unchallenged and VZV challenged skin and did not secrete IFN-gamma 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(+)CD2(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. The Journal of Immunology, 2013, 190: 977-986.
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