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 antigen. 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 antigen re-challenge
in vitro
. VZV-specific T cells, mainly of a central memory (CD45RA
−
CD27
+
) phenotype, accumulate at the site of skin challenge compared to the blood of the same individuals. This resulted in part from local proliferation since >50% of tetramer defined antigen-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 re-stimulation. The CD4
+
Foxp3
+
T cells from unchallenged skin had suppressive activity, since their removal led to an increase in cytokine secretion after activation. After VZV antigen 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 since 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 antigen-specific CD4
+
T cells and CD4
+
Tregs that may provide controlled responsiveness during antigen-specific stimulation in tissues.