l-Arginine modulates CD3ζ expression and T cell function in activated human T lymphocytes

Zea, Arnold H.; Rodríguez, Paulo C.; Culotta, Kirk S.; Hernandez, Claudia; DeSalvo, Joanna; Ochoa, Juan B.; Park, Hae-Joon; Zabaleta, Jovanny; Ochoa, Augusto C.

doi:10.1016/j.cellimm.2005.01.004

Cited by 194 publications

(179 citation statements)

References 46 publications

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“…Similar to observations resulting from Trp metabolism, Arg catabolism was proposed as a mechanism involved in fetal tolerance, after ARG1 activity was shown to be increased in normal term pregnancy (29). Increased Arg catabolism induced T cell hyporesponsiveness through a mechanism involving reduced half-life of mRNA encoding the TCR CD3j chain (30).…”

Section: Discussionmentioning

confidence: 69%

Amino Acid Catabolism in Multiple Sclerosis Affects Immune Homeostasis

Negrotto

Correale

2017

The Journal of Immunology

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Amino acid catabolism has been implicated in immunoregulatory mechanisms present in several diseases, including autoimmune disorders. Our aims were to assess expression and activity of enzymes involved in Trp and Arg catabolism, as well as to investigate amino acid catabolism effects on the immune system of multiple sclerosis (MS) patients. To this end, 40 MS patients, 30 healthy control subjects, and 30 patients with other inflammatory neurological diseases were studied. Expression and activity of enzymes involved in Trp and Arg catabolism (IDO1, IDO2, Trp 2,3-dioxygenase [TDO], arginase [ARG] 1, ARG2, inducible NO synthetase) were evaluated in PBMCs. Expression of general control nonrepressed 2 serine/threonine kinase and mammalian target of rapamycin (both molecules involved in sensing amino acid levels) was assessed in response to different stimuli modulating amino acid catabolism, as were cytokine secretion levels and regulatory T cell numbers. The results demonstrate that expression and activity of IDO1 and ARG1 were significantly reduced in MS patients compared with healthy control subjects and other inflammatory neurological diseases. PBMCs from MS patients stimulated with a TLR-9 agonist showed reduced expression of general control nonrepressed 2 serine/threonine kinase and increased expression of mammalian target of rapamycin, suggesting reduced amino acid catabolism in MS patients. Functionally, this reduction resulted in a decrease in regulatory T cells, with an increase in myelin basic protein–specific T cell proliferation and secretion of proinflammatory cytokines. In contrast, induction of IDO1 using CTLA-4 or a TLR-3 ligand dampened proinflammatory responses. Overall, these results highlight the importance of amino acid catabolism in the modulation of the immunological responses in MS patients. Molecules involved in these pathways warrant further exploration as potential new therapeutic targets in MS.

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Section: Discussionmentioning

confidence: 69%

Amino Acid Catabolism in Multiple Sclerosis Affects Immune Homeostasis

Negrotto

Correale

2017

The Journal of Immunology

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“…Arginase I is an enzyme that converts the amino acid L-arginine to ornithine and urea, which inhibits T cell proliferation and functions in coordination with TGF-h. Furthermore, L-arginine is metabolized to nitric oxide and hydroxide by inducible nitric oxide synthase; the metabolites inhibit Th1 cytokine production and T cell function, and decrease expression of the T cell receptor-( TCR-~) that leads to T cell apoptosis (46). Thus, VEGF-induced iMCs play a critical role in inhibiting innate and adaptive immune responses in cancer cells.…”

Section: Role Of Vegf and Imcs In Immune Evasionmentioning

confidence: 99%

Tumor-Driven Evolution of Immunosuppressive Networks during Malignant Progression

Kim¹,

et al. 2006

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Tumors evolve mechanisms to escape immune control by a process called immune editing, which provides a selective pressure in the tumor microenvironment that could lead to malignant progression. A variety of tumor-derived factors contribute to the emergence of complex local and regional immunosuppressive networks, including vascular endothelial growth factor, interleukin-10, transforming growth factor-B, prostaglandin E 2 , and soluble phosphatidylserine, soluble Fas, soluble Fas ligand, and soluble MHC class I-related chain A proteins. Although deposited at the primary tumor site, these secreted factors could extend immunosuppressive effects into the local lymph nodes and the spleen, promoting invasion and metastasis. Vascular endothelial growth factors play a key role in recruiting immature myeloid cells from the bone marrow to enrich the microenvironment as tumor-associated immature dendritic cells and tumor-associated macrophages. The understanding of the immunosuppressive networks that evolve is incomplete, but several features are emerging. Accumulation of tumor-associated immature dendritic cells may cause roving dendritic cells and T cells to become suppressed by the activation of indoleamine 2,3-dioxygenase and arginase I by tumor-derived growth factors. Soluble phosphatidylserines support tumor-associated macrophages by stimulating the release of anti-inflammatory mediators that block antitumor immune responses. Soluble Fas, soluble FasL, and soluble MHC class I-related chain A proteins may help tumor cells escape cytolysis by cytotoxic T cells and natural killer cells, possibly by counterattacking immune cells and causing their death. In summary, tumor-derived factors drive the evolution of an immunosuppressive network which ultimately extends immune evasion from the primary tumor site to peripheral sites in patients with cancer. (Cancer Res 2006; 66(11): 5527-36)

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“…Эти последствия от-менялись в случае введения экзогенного арги-нина. Культивирование Т-лимфоцитов в среде с концентрацией L-аргинина < 50 μM приводи-ло к существенному снижению пролиферации клеток, а T-лимфоциты, активированные в куль-туральной среде, не содержащей аргинин, име-ли все изменения, ранее описанные у мышей с опухолями и онкологических больных (сни-женную экспрессию (CD3ζ) цепи Т-клеточного рецептора, снижение экспрессии тирозинкиназ p56lck, p59fyn, неспособность запускать Jak-3 внутриклеточный сигнальный путь и отсутствие транслокации транскрипционого фактора NFkB p65 в ядро [118]). При этом супрессорный эф-фект, индуцированный деплецией аргинина, не был связан со снижением трансдукции сигна-ла от Т-клеточного рецептора, т.к.…”

Section: влияние дефицита аргинина на функции т-лимфоцитовunclassified