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

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

doi:10.1172/jci.insight.129756

Cited by 68 publications

(66 citation statements)

References 74 publications

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“…Tregs can be found in several healthy human tissues such as the intestine, skin, adipose tissue, and skeletal muscle (48). In healthy human skin, arginase 2 expression was found as a feature of resident Tregs (67). Whether Tregs can establish long-term residency in these tissues and whether this process may be modified in pathologic conditions remain unclear.…”

Section: Tissue Regulatory T Cells: Resident or Recirculating?mentioning

confidence: 99%

“…Tumor Tregs display a gene signature that combines tissue-specific and tumor-specific genes [reviewed in (69)], and a "core signature" is shared among Tregs infiltrating diverse human cancers (70). In human melanoma, Tregs express a higher level of arginase 2 than in healthy skin (67), suggesting that tumor Tregs may co-opt and enforce signals that preexisted in Tregs resident in the normal parenchyma. In human breast cancer and colon cancer, tumor Tregs were much more similar to the corresponding healthy tissue Tregs than to circulating Tregs (71,72).…”

Section: Tissue Regulatory T Cells: Resident or Recirculating?mentioning

confidence: 99%

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Recirculation and Residency of T Cells and Tregs: Lessons Learnt in Anacapri

2020

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Location, location, and location": according to this mantra, the place where living beings settle has a key impact on the success of their activities; in turn, the living beings can, in many ways, modify their environment. This idea has now become more and more true for T cells. The ability of T cells to recirculate throughout blood or lymph, or to stably reside in certain tissues, turned out to determine immunity to pathogens, and tumors. If location matters also for human beings, the inspiring environment of Capri Island has contributed to the success of the EFIS-EJI Ruggero Ceppellini Advanced School of Immunology focused on "T cell memory," held in Anacapri from October 12, 2018 to October 15, 2018. In this minireview, we would like to highlight some novel concepts about T cell migration and residency and discuss their implications in relation to recent advances in the field, including the mechanisms regulating compartmentalization and cell cycle entry of T cells during activation, the role of mitochondrial metabolism in T cell movement, and the residency of regulatory T cells.

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Section: Tissue Regulatory T Cells: Resident or Recirculating?mentioning

confidence: 99%

Section: Tissue Regulatory T Cells: Resident or Recirculating?mentioning

confidence: 99%

Recirculation and Residency of T Cells and Tregs: Lessons Learnt in Anacapri

2020

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“…Inhibition of mTOR signaling by rapamycin or amino acid depletion was shown to induce FoxP3, but L-arg deficiency was effective only when TGFβ was added (207). Moreover, ARG2 was found in Tregs from normal skin and its expression increased in metastatic melanoma (225). ARG2 in Tregs was demonstrated to attenuate mTOR activity and conferred Tregs with enhanced suppressive activity (225) suggesting that low intracellular L-arg concentrations may facilitate Tregs development.…”

Section: Role Of L-arg In T-cell Differentiationmentioning

confidence: 99%

Myeloid Cell-Derived Arginase in Cancer Immune Response

et al. 2020

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Amino acid metabolism is a critical regulator of the immune response, and its modulating becomes a promising approach in various forms of immunotherapy. Insufficient concentrations of essential amino acids restrict T-cells activation and proliferation. However, only arginases, that degrade L-arginine, as well as enzymes that hydrolyze L-tryptophan are substantially increased in cancer. Two arginase isoforms, ARG1 and ARG2, have been found to be present in tumors and their increased activity usually correlates with more advanced disease and worse clinical prognosis. Nearly all types of myeloid cells were reported to produce arginases and the increased numbers of various populations of myeloid-derived suppressor cells and macrophages correlate with inferior clinical outcomes of cancer patients. Here, we describe the role of arginases produced by myeloid cells in regulating various populations of immune cells, discuss molecular mechanisms of immunoregulatory processes involving L-arginine metabolism and outline therapeutic approaches to mitigate the negative effects of arginases on antitumor immune response. Development of potent arginase inhibitors, with improved pharmacokinetic properties, may lead to the elaboration of novel therapeutic strategies based on targeting immunoregulatory pathways controlled by L-arginine degradation.

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“…92 In humans, the mitochondrial protein arginase 2 (Arg2) is also preferentially expressed in skin Tregs, relative to skin Teffs or circulating Tregs. 93 Using CRISPR-Cas9-mediated ARG2 deletion, the authors concluded that Tregs use this pathway to maintain a tissuespecific signature. 93…”

Section: Skin Tregsmentioning

confidence: 99%

“…93 Using CRISPR-Cas9-mediated ARG2 deletion, the authors concluded that Tregs use this pathway to maintain a tissuespecific signature. 93…”

Section: Skin Tregsmentioning

confidence: 99%

Tissue regulatory T cells

Cho

Ali

2020

Immunology

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Summary Foxp3+ CD4+ regulatory T cells (Tregs) are an immune cell lineage endowed with immunosuppressive functionality in a wide array of contexts, including both anti‐pathogenic and anti‐self responses. In the past decades, our understanding of the functional diversity of circulating or lymphoid Tregs has grown exponentially. Only recently, the importance of Tregs residing within non‐lymphoid tissues, such as visceral adipose tissue, muscle, skin and intestine, has been recognized. Not only are Tregs critical for influencing the kinetics and strength of immune responses, but the regulation of non‐immune or parenchymal cells, also fall within the purview of tissue‐resident or infiltrating Tregs. This review focuses on providing a systematic and comprehensive comparison of the molecular maintenance, local adaptation and functional specializations of Treg populations operating within different tissues.

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

Cited by 68 publications

References 74 publications

Recirculation and Residency of T Cells and Tregs: Lessons Learnt in Anacapri

Recirculation and Residency of T Cells and Tregs: Lessons Learnt in Anacapri

Myeloid Cell-Derived Arginase in Cancer Immune Response

Tissue regulatory T cells

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