Aiolos and Eos drive distinct human TH17 functional states

CD4+ T helper (TH)-17 cells play a pivotal role in mucosal immune defense and are implicated in autoimmune diseases and cancer. Although Th17 cell plasticity is well-studied in mice, the factors driving their transition between pro-inflammatory and immunomodulatory states in humans remain less understood. Our study explored the transcriptional and epigenetic landscapes of single-cell cultures of human memory TH17 cells, focusing on clones that produce either immunomodulatory IL-10 or pro-inflammatory IFNγ and IL-22. We found that IL-10+ TH17 cells exhibit a T cell exhaustion-like profile with increased CTLA-4 expression and reduced IL-2 levels, while Ikaros zinc finger (IkZF) transcription factors, Aiolos and Eos, are differentially expressed in IL-10+ and IL-22+ TH17 cells, respectively. While exogenous IL-2 promotes IL-10 production in TH17 cells, lenalidomide induces IL-2 and promotes inflammatory TH17 cells, shifting TH17 cells towards a pro-inflammatory phenotype by reducing IL-10 and increasing IL-22 and IFNγ levels. Conversely, upregulation of Eos enhanced pro-inflammatory cytokine production. These findings highlight the crucial role of IkZF transcription factors in regulating human TH17 cell functions. Moreover, single-cell RNA sequencing of PBMCs from lenalidomide-treated patients confirmed an enrichment of inflammatory signatures, including interferon and IL-2/STAT5 pathways in TH17 cells. The ability to modulate this axis through targeted interventions, such as lenalidomide-induced Aiolos degradation or enforced Eos expression, presents new therapeutic opportunities for managing TH17 cell states in cancer and autoimmune diseases.

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Publication Details

Journal
Cellular and Molecular Life Sciences
Published
2026-04-01
DOI
https://doi.org/10.1007/s00018-026-06089-1
Primary Topic
Psoriasis: Treatment and Pathogenesis
Type
article
Field-Weighted Citation Impact
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article

Aiolos and Eos drive distinct human TH17 functional states

Elisabeth Israelsson, Malo Leprohon, Hanna Grindebacke, Ulf Gehrmann et al.
Cellular and Molecular Life Sciences
Psoriasis: Treatment and Pathogenesis
article

Aiolos and Eos drive distinct human TH17 functional states

Elisabeth Israelsson, Malo Leprohon, Hanna Grindebacke, Ulf Gehrmann, Karin Tarte, Bingyu Yan, Suman Mitra, Zonghao Zhang, Silvia Gaggero, Mojtaba Shekarkar Azgomi, Majid Kazemian, Salomon Manier, Ramachandramouli Budida, Arian Laurence, Chrystal Mary Paulos, Ilenia Papa, Marcello Maresca, Anja Mezger, Eva Cáceres, Anna Rudin, Mike Firth, Silvia Cerboni, Leila Mohammadnezhad, Leif Wigge, A. C Cole, F. Morschhauser, Songyuan Li, Michael Hühn, Joel Dulong, Komal Agrawal, Svitlana Salemio, Petr Volkov, Yue Cui
article en

Abstract

CD4+ T helper (TH)-17 cells play a pivotal role in mucosal immune defense and are implicated in autoimmune diseases and cancer. Although Th17 cell plasticity is well-studied in mice, the factors driving their transition between pro-inflammatory and immunomodulatory states in humans remain less understood. Our study explored the transcriptional and epigenetic landscapes of single-cell cultures of human memory TH17 cells, focusing on clones that produce either immunomodulatory IL-10 or pro-inflammatory IFNγ and IL-22. We found that IL-10+ TH17 cells exhibit a T cell exhaustion-like profile with increased CTLA-4 expression and reduced IL-2 levels, while Ikaros zinc finger (IkZF) transcription factors, Aiolos and Eos, are differentially expressed in IL-10+ and IL-22+ TH17 cells, respectively. While exogenous IL-2 promotes IL-10 production in TH17 cells, lenalidomide induces IL-2 and promotes inflammatory TH17 cells, shifting TH17 cells towards a pro-inflammatory phenotype by reducing IL-10 and increasing IL-22 and IFNγ levels. Conversely, upregulation of Eos enhanced pro-inflammatory cytokine production. These findings highlight the crucial role of IkZF transcription factors in regulating human TH17 cell functions. Moreover, single-cell RNA sequencing of PBMCs from lenalidomide-treated patients confirmed an enrichment of inflammatory signatures, including interferon and IL-2/STAT5 pathways in TH17 cells. The ability to modulate this axis through targeted interventions, such as lenalidomide-induced Aiolos degradation or enforced Eos expression, presents new therapeutic opportunities for managing TH17 cell states in cancer and autoimmune diseases.

Cellular and Molecular Life SciencesVol. 83(1)
AstraZeneca (United Kingdom) (GB), Centre National de la Recherche Scientifique (FR), Emory University (US), Inserm (FR), Purdue University West Lafayette (US), Institut Pasteur de Lille (FR), John Radcliffe Hospital (GB), Centre Hospitalier Universitaire de Lille (FR), Centre de Recherche en Cancérologie de Lyon (FR), AstraZeneca (Finland) (FI), AstraZeneca (Sweden) (SE), AstraZeneca (Spain) (ES), Microenvironment and B-cells: Immunopathology, Cell, Differentiation and Cancer (FR), University of Gothenburg (SE)
Good health and well-being
Openalex Percentile: Top 40%
Psoriasis: Treatment and Pathogenesis
DOIOpen Access PDFOpenAlex
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