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<p>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.</p>

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Aiolos and Eos drive distinct human TH17 functional states

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月1日

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

摘要

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.