The immunosuppressive enzyme IL4I1 promotes FoxP3+ regulatory T lymphocyte differentiation

IL4I1 (interleukin‐4‐induced gene 1) is a phenylalanine oxidase produced mainly by APCs of myeloid origin, and converts phenylalanine (Phe) to phenylpyruvate, hydrogen peroxide, and ammonia. We have previously shown that IL4I1 is highly expressed by tumor‐associated macrophages from various human cancers and facilitates immune evasion from the cytotoxic response in a murine tumor model. Indeed, IL4I1 inhibits T‐cell proliferation via hydrogen peroxide toxicity on effector/memory T cells. Here, we explored the effect of IL4I1 on naïve CD4⁺ T‐cell differentiation. We show that IL4I1 stimulates the generation of Foxp3⁺ regulatory T (Treg) cells in vitro from human and mouse T cells. This effect was observed with IL4I1 from different sources, including the naturally produced enzyme. Conversely, IL4I1 limits Th1 and Th2 polarization while modifying the Th17 phenotype, in particular, by inducing its own production. Analysis of Treg‐cell induction under conditions of Phe deprivation and hydrogen peroxide addition suggests that Phe consumption by the enzyme participates in Treg‐cell enrichment. In line with this hypothesis, IL4I1 inhibits mTORC1 signaling shortly after T‐cell activation. Thus, the IL4I1 enzyme may act on T cells both by direct inhibition of effector cell proliferation and by indirect immunoregulation mediated by Treg‐cell induction.