l-Arginine-Dependent Epigenetic Regulation of Interleukin-10, but Not Transforming Growth Factor-β, Production by Neonatal Regulatory T Lymphocytes

Abstract

A growing number of diseases in humans, including trauma, certain cancers, and infection, are known to be associated with l-arginine deficiency. In addition, l-arginine must be supplemented by diet during pregnancy to aid fetal development. In conditions of l-arginine depletion, T cell proliferation is impaired. We have previously shown that neonatal blood has lower l-arginine levels than adult blood, which is associated with poor neonatal lymphocyte proliferation, and that l-arginine enhances neonatal lymphocyte proliferation through an interleukin (IL)-2-independent pathway. In this study, we have further investigated how exogenous l-arginine enhances neonatal regulatory T-cells (Tregs) function in relation to IL-10 production under epigenetic regulation. Results showed that cord blood mononuclear cells (CBMCs) produced higher levels of IL-10 than adult peripheral blood mononuclear cells (PBMCs) by phytohemagglutinin stimulation but not by anti-CD3/anti-CD28 stimulation. Addition of exogenous l-arginine had no effect on transforming growth factor-β production by PBMCs or CBMCs, but enhanced IL-10 production by neonatal CD4+CD25+FoxP3+ Tregs. Further studies showed that IL-10 promoter DNA hypomethylation, rather than histone modification, corresponded to the l-arginine-induced increase in IL-10 production by neonatal CD4+ T cells. These results suggest that l-arginine modulates neonatal Tregs through the regulation of IL-10 promoter DNA methylation. l-arginine supplementation may correct the Treg function in newborns with l-arginine deficiency.

Myeloid Cell-Derived Arginase in Cancer Immune Response

“…Secretion of several cytokines that play a critical role in Tcell differentiation and effector functions is also diminished in L-arg-starved cells (Figure 5). Conspicuously, this especially refers to the secretion of Th1 cytokines, including IFN-γ and tumor necrosis factor β (TNF-β) (123,214,217), although Tcells cultured in L-arg-free medium also secrete lower amounts of IL-5, and IL-10 as compared with T-cells cultured in complete medium (218). The decrease in IFN-γ secretion is also induced by ARG + tumor-infiltrating DCs (203) and ARG inhibitors administered in vivo increase IFN-γ secretion (219).…”

Regulatory T cell metabolism at the intersection between autoimmune diseases and cancer

“…The absence of either AA in murine Tregs result in a reduced number of activated Tregs and these mice develop fatal autoimmune disease [86]. Lastly, in human CD4 + CD25 + FoxP3 + Tregs, exogenous arginine induces DNA hypomethylation rather than histone modification of the IL‐10 promoter, which leads to higher IL‐10 production by these cells [87].…”

Metabolic adaptation orchestrates tissue context‐dependent behavior in regulatory T cells

“…To meet their metabolic demand for development and maintenance in the liver, Tregs may either directly utilize those metabolites or are affected by the cytokine and chemokine changes in local DCs induced by environmental metabolism. More specifically, glucose and amino acids like arginine and glutamine, mainly absorbed through portal vein, have been shown to influence FoxP3 expression in Tregs by entering into the metabolic tricarboxylic acid (TCA) cycle . Besides, variety of SCFAs such as butyrate and propionic acid and some median chain fatty acids are also enriched in liver, with which exert effect on TGF‐β‐dependent generation of FoxP3 + Tregs, largely via signaling through metabolite‐sensing G protein–coupled receptors (GPCRs) .…”