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 5

Immunosuppressive effect of Kaede-red Tregs in the skin.

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Immunosuppressive effect of Kaede-red Tregs in the skin. (A) Suppression...
(A) Suppression of CHS response by Kaede-red Tregs. Kaede-red or Kaede-green Tregs (4 × 103 cells/ear) of Kaede/Foxp3hCD2/hCD52 mice sensitized, challenged, and photoconverted as in Figure 3A were injected into ear skin of mice sensitized with DNFB 5 days prior. Immediately after injection, the mice were challenged, and the ear thickness change was measured at 48, 72, and 96 hours after challenge. (B–D) The mice were sensitized, challenged, and photoconverted as in Figure 3A. Twenty-four hours after photoconversion, 20 μl of 0.3% DNFB (challenge; +) or vehicle (challenge; –) (B) or 20 μl of 0.3% DNFB or 20 μl of 1% TNCB (C) was painted onto the ear. Twenty-four hours later, the ear skin and blood (D) were collected and dissociated for flow cytometry. The number of Kaede-red Tregs in the skin and the frequency of Kaede-red Tregs in CD4+ T cell subset of the blood were evaluated (n = 3, each group). Data are presented as means ± SD and representative of 3 independent experiments (A–C). Student’s t test was performed between the indicated groups. *P < 0.05. Numbers within plots indicate percentage of cells in the respective areas (D).