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Functional Phenotypic Diversity of Regulatory T Cells Remaining in Inflamed Skin

Regulatory T cells (Tregs) migrate between lymphoid and peripheral tissues for maintaining immune homeostasis. Tissue-specific function and functional heterogeneity of Tregs have been suggested, however, correlation between them and inter-tissue movement remain unknown. We used a contact hypersensit...

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Autores principales: Ikebuchi, Ryoyo, Fujimoto, Maika, Nakanishi, Yasutaka, Okuyama, Hiromi, Moriya, Taiki, Kusumoto, Yutaka, Tomura, Michio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534040/
https://www.ncbi.nlm.nih.gov/pubmed/31156643
http://dx.doi.org/10.3389/fimmu.2019.01098
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author Ikebuchi, Ryoyo
Fujimoto, Maika
Nakanishi, Yasutaka
Okuyama, Hiromi
Moriya, Taiki
Kusumoto, Yutaka
Tomura, Michio
author_facet Ikebuchi, Ryoyo
Fujimoto, Maika
Nakanishi, Yasutaka
Okuyama, Hiromi
Moriya, Taiki
Kusumoto, Yutaka
Tomura, Michio
author_sort Ikebuchi, Ryoyo
collection PubMed
description Regulatory T cells (Tregs) migrate between lymphoid and peripheral tissues for maintaining immune homeostasis. Tissue-specific function and functional heterogeneity of Tregs have been suggested, however, correlation between them and inter-tissue movement remain unknown. We used a contact hypersensitivity model of mice expressing a photoconvertible protein for tracking migratory cells. After marking cells in skin, we purified Tregs exhibiting a different migration pattern [Tregs recruiting to or remaining in the skin and emigrating from the skin to draining lymph nodes (dLNs) within half a day] and examined single-cell gene and protein expression profiles. Correlation and unsupervised clustering analyses revealed that Tregs in both skin and dLNs comprised two subpopulations, one highly expressing Nrp1 with variable CD25, Granzyme B, and/or CTLA-4 expression and another with 3 subsets strongly expressing CD25, Granzyme B, or CTLA-4 together with CD39. Characteristic subsets of Tregs remaining in the skin displayed higher CD25 and CD39 expression and lower Granzyme B and CTLA-4 expression compared with Tregs migrating to the skin. In addition, CCR5 expression in Tregs in skin was positively and negatively correlated with CD39 and Nrp-1 expression, respectively. To assess the predictive value of these data for immunotherapy, we blocked CCR5 signaling and found modest downregulation of CD39 and modest upregulation of Nrp1 expression in skin Tregs. Our data reveal a high functional diversity of Tregs in skin that is strongly related to trafficking behavior, particularly skin retention. Modulation of tissue-specific trafficking and function is a promising clinical strategy against autoimmune, infectious, and neoplastic diseases. SIGNIFICANCE STATEMENT: Regulatory T cells (Tregs) are essential for maintaining immune homeostasis. To reveal tissue-specific immunoinhibitory functions and inter-tissue movement correlation based on Treg functional heterogeneity, we examined single-cell gene and protein expression profiles of Tregs recruited to, remaining in, or emigrating from the contact hypersensitivity-induced inflamed skin. Tregs in skin were composed of several subpopulations; one with high Nrp1 expression and another with 3 subsets strongly expressing CD25, Granzyme B, or CTLA-4 together with CD39. Tregs remaining in skin displayed highCD25, CD39, and CCR5 expression, and CCR5 signaling blockade downregulated CD39. A high Treg functional diversity in skin is strongly related to trafficking behavior. Tissue-specific trafficking and functional modulation are a promising clinical strategy against autoimmune, infectious, and neoplastic diseases.
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spelling pubmed-65340402019-05-31 Functional Phenotypic Diversity of Regulatory T Cells Remaining in Inflamed Skin Ikebuchi, Ryoyo Fujimoto, Maika Nakanishi, Yasutaka Okuyama, Hiromi Moriya, Taiki Kusumoto, Yutaka Tomura, Michio Front Immunol Immunology Regulatory T cells (Tregs) migrate between lymphoid and peripheral tissues for maintaining immune homeostasis. Tissue-specific function and functional heterogeneity of Tregs have been suggested, however, correlation between them and inter-tissue movement remain unknown. We used a contact hypersensitivity model of mice expressing a photoconvertible protein for tracking migratory cells. After marking cells in skin, we purified Tregs exhibiting a different migration pattern [Tregs recruiting to or remaining in the skin and emigrating from the skin to draining lymph nodes (dLNs) within half a day] and examined single-cell gene and protein expression profiles. Correlation and unsupervised clustering analyses revealed that Tregs in both skin and dLNs comprised two subpopulations, one highly expressing Nrp1 with variable CD25, Granzyme B, and/or CTLA-4 expression and another with 3 subsets strongly expressing CD25, Granzyme B, or CTLA-4 together with CD39. Characteristic subsets of Tregs remaining in the skin displayed higher CD25 and CD39 expression and lower Granzyme B and CTLA-4 expression compared with Tregs migrating to the skin. In addition, CCR5 expression in Tregs in skin was positively and negatively correlated with CD39 and Nrp-1 expression, respectively. To assess the predictive value of these data for immunotherapy, we blocked CCR5 signaling and found modest downregulation of CD39 and modest upregulation of Nrp1 expression in skin Tregs. Our data reveal a high functional diversity of Tregs in skin that is strongly related to trafficking behavior, particularly skin retention. Modulation of tissue-specific trafficking and function is a promising clinical strategy against autoimmune, infectious, and neoplastic diseases. SIGNIFICANCE STATEMENT: Regulatory T cells (Tregs) are essential for maintaining immune homeostasis. To reveal tissue-specific immunoinhibitory functions and inter-tissue movement correlation based on Treg functional heterogeneity, we examined single-cell gene and protein expression profiles of Tregs recruited to, remaining in, or emigrating from the contact hypersensitivity-induced inflamed skin. Tregs in skin were composed of several subpopulations; one with high Nrp1 expression and another with 3 subsets strongly expressing CD25, Granzyme B, or CTLA-4 together with CD39. Tregs remaining in skin displayed highCD25, CD39, and CCR5 expression, and CCR5 signaling blockade downregulated CD39. A high Treg functional diversity in skin is strongly related to trafficking behavior. Tissue-specific trafficking and functional modulation are a promising clinical strategy against autoimmune, infectious, and neoplastic diseases. Frontiers Media S.A. 2019-05-17 /pmc/articles/PMC6534040/ /pubmed/31156643 http://dx.doi.org/10.3389/fimmu.2019.01098 Text en Copyright © 2019 Ikebuchi, Fujimoto, Nakanishi, Okuyama, Moriya, Kusumoto and Tomura. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Ikebuchi, Ryoyo
Fujimoto, Maika
Nakanishi, Yasutaka
Okuyama, Hiromi
Moriya, Taiki
Kusumoto, Yutaka
Tomura, Michio
Functional Phenotypic Diversity of Regulatory T Cells Remaining in Inflamed Skin
title Functional Phenotypic Diversity of Regulatory T Cells Remaining in Inflamed Skin
title_full Functional Phenotypic Diversity of Regulatory T Cells Remaining in Inflamed Skin
title_fullStr Functional Phenotypic Diversity of Regulatory T Cells Remaining in Inflamed Skin
title_full_unstemmed Functional Phenotypic Diversity of Regulatory T Cells Remaining in Inflamed Skin
title_short Functional Phenotypic Diversity of Regulatory T Cells Remaining in Inflamed Skin
title_sort functional phenotypic diversity of regulatory t cells remaining in inflamed skin
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534040/
https://www.ncbi.nlm.nih.gov/pubmed/31156643
http://dx.doi.org/10.3389/fimmu.2019.01098
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