The immunosuppressive enzyme IL4I1 promotes FoxP3(+) regulatory T lymphocyte differentiation

European Journal of Immunology
Céline CousinValérie Molinier-Frenkel

Abstract

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 bo...Continue Reading

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Citations

Jan 20, 2016·Nature Immunology·Peter J Murray
Mar 25, 2016·Molecular Immunology·Rudolf BicheleMartti Laan
Oct 12, 2016·European Journal of Immunology·Sergio Romagnani
Nov 1, 2016·Brain : a Journal of Neurology·Konstantina PsachouliaJeffrey K Huang
Dec 31, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Lloyd BodArmelle Prévost-Blondel
Aug 10, 2017·FEBS Letters·Valérie Molinier-Frenkel, Flavia Castellano
Dec 6, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Flavia Castellano, Valérie Molinier-Frenkel
Jul 25, 2019·Cells·Valérie Molinier-FrenkelFlavia Castellano
Apr 14, 2017·Oncoimmunology·Lloyd BodArmelle Prévost-Blondel
Jan 5, 2021·Frontiers in Cell and Developmental Biology·Flavia Castellano, Valérie Molinier-Frenkel
Mar 2, 2021·ELife·Leonie ZeitlerPeter J Murray
May 25, 2021·Oncoimmunology·Flavia CastellanoValérie Molinier-Frenkel
Jun 10, 2021·Applied Microbiology and Biotechnology·Kosuke KasaiTomisato Miura

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