Regulatory T cells use arginase 2 to enhance their metabolic fitness in tissues
Margaret M. Lowe, … , Tiffany C. Scharschmidt, Michael D. Rosenblum
Margaret M. Lowe, … , Tiffany C. Scharschmidt, Michael D. Rosenblum
Published December 19, 2019
Citation Information: JCI Insight. 2019;4(24):e129756. https://doi.org/10.1172/jci.insight.129756.
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Research Article Immunology Metabolism

Regulatory T cells use arginase 2 to enhance their metabolic fitness in tissues

Abstract

Distinct subsets of Tregs reside in nonlymphoid tissues where they mediate unique functions. To interrogate the biology of tissue Tregs in human health and disease, we phenotypically and functionally compared healthy skin Tregs with those in peripheral blood, inflamed psoriatic skin, and metastatic melanoma. The mitochondrial enzyme, arginase 2 (ARG2), was preferentially expressed in Tregs in healthy skin, increased in Tregs in metastatic melanoma, and reduced in Tregs from psoriatic skin. ARG2 enhanced Treg suppressive capacity in vitro and conferred a selective advantage for accumulation in inflamed tissues in vivo. CRISPR-mediated deletion of this gene in primary human Tregs was sufficient to skew away from a tissue Treg transcriptional signature. Notably, the inhibition of ARG2 increased mTOR signaling, whereas the overexpression of this enzyme suppressed it. Taken together, our results suggest that Tregs express ARG2 in human tissues to both regulate inflammation and enhance their metabolic fitness.

Authors

Margaret M. Lowe, Ian Boothby, Sean Clancy, Richard S. Ahn, Wilson Liao, David N. Nguyen, Kathrin Schumann, Alexander Marson, Kelly M. Mahuron, Gillian A. Kingsbury, Zheng Liu, Priscila Munoz Sandoval, Robert Sanchez Rodriguez, Mariela L. Pauli, Keyon Taravati, Sarah T. Arron, Isaac M. Neuhaus, Hobart W. Harris, Esther A. Kim, Uk Sok Shin, Matthew F. Krummel, Adil Daud, Tiffany C. Scharschmidt, Michael D. Rosenblum

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Figure 1

Arginase 2 is highly expressed in Tregs in healthy human skin and reduced in Tregs in psoriatic skin.

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Arginase 2 is highly expressed in Tregs in healthy human skin and reduce...
(A) Flow cytometric plot depicting FOXP3 expression in human skin CD25+CD27+ sort-purified Tregs (1) and CD25–CD27– sort-purified Teffs (2). (B) Principal component analysis (PCA) of RNA-Seq data from sort-purified Tregs and CD4+ effector T cells (Teffs) from 5 healthy skin samples and 5 psoriasis (PSO) skin lesions. (C) Heat map of significantly different gene counts (normalized by row) comparing healthy human skin Tregs with Tregs from PSO lesions (P < 0.05, Wald test). (D) Log2 fold change of genes differentially expressed in both healthy Tregs, compared with healthy skin Teffs, and PSO skin Tregs, compared with healthy skin Tregs (P < 0.05, minimum Treg expression > 200 normalized counts). (E) Normalized RNA-Seq counts of samples depicted in A (*P < 0.05, Wald test). (F) PCA analysis of RNA-Seq data from Tregs, CD4+ Teffs, CD8+ T cells, dendritic cells (DC), and keratinocytes (KC) isolated from healthy human skin (10 donors). (G) Normalized RNA-Seq counts of cells depicted in F (***P < 0.001, ordinary 1-way ANOVA, Dunnett’s multiple comparisons test).