RESUMO
IL4I1 encodes an L-phenylalanine oxidase that inhibits T-cell proliferation. It has been recently reported that IL4I1 is expressed in TH17 cells as part of a mechanism that limits their pathogenicity. We have previously identified a population of human FOXP3(+) Treg cells that secrete IL-17 ex vivo; here, we addressed the expression of IL4I1 in that Treg-cell population. We found that in ex vivo isolated circulating Treg cells, IL4I1 expression is induced by activation. Moreover, IL4I1 expression is restricted to cells that do not express Helios, a transcription factor that characterizes natural Treg cells, but that express Aiolos, which is involved in the differentiation of TH17 and induced Treg cells. We also showed that conversion of Treg cells under inflammatory conditions increases IL4I1 expression, likely as part of a regulatory loop that attempts to limit the pathogenicity resulting from their conversion into TH17. The specific expression of IL4I1 in TH17 and iTreg cells may provide insights into approaches that aim at modulating these populations in different pathological conditions involving inflammation-mediated immunosuppression.
Assuntos
Fatores de Transcrição Forkhead/genética , Fator de Transcrição Ikaros/genética , L-Aminoácido Oxidase/genética , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Comunicação Celular , Diferenciação Celular , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica/imunologia , Humanos , Fator de Transcrição Ikaros/imunologia , Tolerância Imunológica , Interleucina-17/genética , Interleucina-17/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Ionomicina/farmacologia , L-Aminoácido Oxidase/imunologia , Ativação Linfocitária , Transdução de Sinais , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Acetato de Tetradecanoilforbol/farmacologia , Células Th17/citologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/imunologiaRESUMO
FOXP3(+) regulatory T cells (Tregs) are critical regulators of self-tolerance and immune homeostasis. In mice and humans, two subsets of FOXP3(+) Tregs have been defined based on their differential expression of Helios, a transcription factor of the Ikaros family. Whereas the origin, specificity, and differential function of the two subsets are as yet a source of controversy, their characterization thus far has been limited by the absence of surface markers to distinguish them. In this article, we show that human memory Helios(+) and Helios(-) Tregs are phenotypically distinct and can be separated ex vivo based on their differential expression of IL-1RI, which is restricted to Helios(-) Tregs, in combination with CCR7. The two populations isolated using this strategy are distinct with respect to the expression of other Ikaros family members. Namely, whereas Eos, which has been reported to mediate FOXP3-dependent gene silencing, is expressed in Helios(+) Tregs, Aiolos, which is involved in the differentiation of TH17 and induced Tregs, is instead expressed in Helios(-) Tregs. In addition, whereas both subsets are suppressive ex vivo, Helios(-) Tregs display increased suppressive capacity in comparison to Helios(+) Tregs, but respond to IL-1ß by downregulating their suppressive activity. Together, these data support the concept that human Helios(-) memory Tregs encompass induced Tregs that can readily respond to changes in the environment by modulating their suppressive capacity.
