Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice
Michio Tomura, … , Osami Kanagawa, Kenji Kabashima
Michio Tomura, … , Osami Kanagawa, Kenji Kabashima
Published February 22, 2010
Citation Information: J Clin Invest. 2010;120(3):883-893. https://doi.org/10.1172/JCI40926.
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Research Article

Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice

Abstract

Tregs play an important role in protecting the skin from autoimmune attack. However, the extent of Treg trafficking between the skin and draining lymph nodes (DLNs) is unknown. We set out to investigate this using mice engineered to express the photoconvertible fluorescence protein Kaede, which changes from green to red when exposed to violet light. By exposing the skin of Kaede-transgenic mice to violet light, we were able to label T cells in the periphery under physiological conditions with Kaede-red and demonstrated that both memory phenotype CD4+Foxp3– non-Tregs and CD4+Foxp3+ Tregs migrated from the skin to DLNs in the steady state. During cutaneous immune responses, Tregs constituted the major emigrants and inhibited immune responses more robustly than did LN-resident Tregs. We consistently observed that cutaneous immune responses were prolonged by depletion of endogenous Tregs in vivo. In addition, the circulating Tregs specifically included activated CD25hi Tregs that demonstrated a strong inhibitory function. Together, our results suggest that Tregs in circulation infiltrate the periphery, traffic to DLNs, and then recirculate back to the skin, contributing to the downregulation of cutaneous immune responses.

Authors

Michio Tomura, Tetsuya Honda, Hideaki Tanizaki, Atsushi Otsuka, Gyohei Egawa, Yoshiki Tokura, Herman Waldmann, Shohei Hori, Jason G. Cyster, Takeshi Watanabe, Yoshiki Miyachi, Osami Kanagawa, Kenji Kabashima

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Figure 2

Migration of Tregs from the skin to DLNs.

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Migration of Tregs from the skin to DLNs. (A–E) The DLN cells of Kaede/F...
(A–E) The DLN cells of Kaede/Foxp3hCD2/hCD52 mice photoconverted on the abdomen 24 hours prior were stained with CD4, CD25, and hCD2 mAbs. Shown here are the flow cytometric plots for hCD2/Foxp3 and CD25 staining among CD4+ cells (A) and Kaede-red and Kaede-green expression on hCD2+CD4+ cells among skin DLN cells (B). (C) The DLNs and non-DLNs from the mice 24 hours after photoconversion were stained with CD4, hCD2, and CD44 mAbs and subjected to flow cytometry. (D) hCD2/Foxp3 expression in total (Kaede-red plus Kaede-green), Kaede-red, and Kaede-green CD4 cells was compared by flow cytometry. (E) The numbers of CD44mid naive (M), CD44hi memory (H), and naive plus memory (H/M) phenotypes of hCD2–CD4+ non-Tregs (–), hCD2+CD4+ Tregs (+), and total (hCD2– and hCD2+; +/–) CD4+ T cells in total CD4+ (Kaede-red plus Kaede-green) cells and Kaede-red cells in the DLNs were counted. Data are presented as means ± SD and are representative of 3 independent experiments. Student’s t test was performed between the indicated groups. *P < 0.05. Numbers within plots or histograms indicate percentage of cells in the respective areas (A–D).