Abstract
The cytokine interleukin IL‐35 is known to exert strong immunosuppressive functions. Indoleamine 2,3‐dioxygenase 1 (IDO1) and Arginase 1 (Arg1) are metabolic enzymes that, expressed by dendritic cells (DCs), contribute to immunoregulation. Here, we explored any possible link between IL‐35 and the activity of those enzymes. We transfected a single chain IL‐35Ig gene construct in murine splenic DCs (DC 35) and assessed any IDO1 and Arg1 activities as resulting from ectopic IL‐35Ig expression, both in vitro and in vivo. Unlike Ido1, Arg1 expression was induced in vitro in DC 35, and it conferred an immunosuppressive phenotype on those cells, as revealed by a delayed‐type hypersensitivity assay. Moreover, the in vivo onset of a tolerogenic phenotype in DC 35 was associated with the detection of CD25+ CD39+, rather than Foxp3+, regulatory T cells. Therefore, Arg1, but not Ido1, expression in DC 35 appears to be an early event in IL‐35Ig–mediated immunosuppression.
Highlights
The control of immune response is operated by specialized cells, sol‐ uble molecules and membrane‐bound signals, which modulate the intensity of immune reactivity and preside over the maintenance of homoeostasis
We investigated the possible role of IDO1 and Arg[1] enzymes as potential immunometabolic effectors down‐ stream of the tolerogenic action of IL‐35Ig in splenic CD8α− Dendritic cells (DCs)
As the increased expression of the amino acid degrad‐ ing enzymes IDO1 and/or Arg[1] is a critical condition for the acqui‐ sition of suppressive functions by DCs, we investigated the possible induction of the two enzymes as a consequence of IL‐35Ig ectopic expression
Summary
The control of immune response is operated by specialized cells, sol‐ uble molecules and membrane‐bound signals, which modulate the intensity of immune reactivity and preside over the maintenance of homoeostasis. In CD8α− DCs, the increased metabolism of specific amino acids and the subsequent produc‐ tion of regulatory catabolites critically contribute to the acqui‐ sition of a newly expressed suppressive phenotype. Interleukin‐35 is a heterodimeric cytokine belonging in the IL‐12 family It powerfully dampens immune responses by suppressing T‐cell proliferation and inducing the expansion of specific subsets of Tregs and regulatory B cells. IDO1 degrades the essential amino acid l‐tryptophan to l‐kynurenine. L‐kynurenine is an endogenous agonist of the Aryl Hydrocarbon Receptor, promoting the expansion of Treg cells and acting to up‐regulate Ido[1] expression in a feedforward loop in DCs.[10]. We investigated the possible role of IDO1 and Arg[1] enzymes as potential immunometabolic effectors down‐ stream of the tolerogenic action of IL‐35Ig in splenic CD8α− DCs
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