Suppression of T-cell functions by human granulocyte arginase

Abstract

Chronic inflammation is accompanied by impaired T-cell immunity. In the mouse, myeloid cell-associated arginase accounts for the suppression of immune reactivity in various models of tumor growth and chronic infections. Here we show that arginase I is liberated from human granulocytes, and very high activities accumulate extracellularly during purulent inflammatory reactions. Human granulocyte arginase induces a profound suppression of T-cell proliferation and cytokine synthesis. This T-cell phenotype is due to arginase-mediated depletion of arginine in the T-cell environment, which leads to CD3 chain down-regulation but does not alter T-cell viability. Our study therefore demonstrates that human granulocytes possess a previously unanticipated immunosuppressive effector function. Human granulocyte arginase is a promising pharmacologic target to reverse unwanted immunosuppression.

A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

“…diminished production of IFN-g and downstream effectors, is most relevant for the failure of IL-18 KO mice to control mycobacteria. Arginase-1 has also been detected in PMN [28,29]. Thus, the vast number of PMN in IL-18 KO lungs represents an additional or alternative source for arginase-1.…”

“…Both IL-18 and MyD88 KO lungs show diminished expression of TNF-b, which is directly involved in organization of granulomas in mycobacterial infection [13]. Furthermore, up-regulation of arginase-1 could result in a negative nitrogen balance within the lung tissue by depletion of arginine, which is an important micronutrient for T-cell proliferation and cytokine synthesis [29,35]. The strong influx of metabolically active cells may further deplete micronutrient sources [36].…”

Neutrophil‐lymphocyte ratio at diagnosis is an independent prognostic factor in patients with nodular sclerosis Hodgkin lymphoma: results of a large multicenter study involving 990 patients

“…The reason for this correlation of NLR with poor prognosis is largely unknown. However, in this respect it has been reported that normal neutrophils are able to suppress T‐cell function, while activated neutrophils have increased levels of arginase 1, which also cause T‐cell suppression 20. In addition to contributing to T‐cell immune suppression, neutrophils may also exhibit tumor‐promoting capabilities, like the induction of angiogenesis and enhancement of tumor spread by enhancing the expression of matrix metalloproteinase 9 10…”

Infectious tolerance via the consumption of essential amino acids and mTOR signaling

“…Although the local consumption of multiple EAAs would seem to represent a redundant and therefore functionally robust system, each individual enzyme probably has additional specialized immunomodulatory properties. For example, IDO appears to be primarily expressed within APCs, requiring the appropriate tryptophan transporters to achieve extracellular depletion of tryptophan (24), whereas arginase can be secreted by neutrophils to deplete extracellular arginine (25). There are also specific functions for some of the products of amino acid consumption, such as kynurenines generated from tryptophan by IDO and NO generated by iNOS from arginine.…”