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<p>Conventional dendritic cells (cDCs) are key sentinels at epithelial barriers, regulating immunity to microbial pathogens and commensals while preserving tissue integrity. NOTCH2 deficiency in CD11c-expressing cells (<i>Notch2</i><sup>cKO</sup>) disrupts type 2a DC (cDC2a) development, impairs intestinal T<sub>H</sub>17 immunity and increases susceptibility to enteropathogenic bacteria. This defect leads to persistent dysbiosis in <i>Notch2</i><sup>cKO</sup> mice, characterized by low-grade inflammation and systemic autoimmune features, including elevated autoantibody titers and renal immune complex deposition. Dysbiosis precedes expansion of highly inflammatory AXL-expressing type 3 DCs (AXL<sup>+</sup>inf-DC3), promoting chronic inflammation and tertiary lymphoid structures driving adaptive immune responses. Notably, dysbiosis is defined by three dominant pathobionts and is transferable to wild-type mice, recapitulating the autoimmune features observed in <i>Notch2</i><sup>cKO</sup> mice. Here these findings identify a microbiota–DC axis linking intestinal pathobionts to systemic autoimmunity, establishing inflammatory DC3 as the cellular bridge between dysbiosis, chronic inflammation and autoimmune pathogenesis.</p>

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Dysbiosis-induced expansion of AXL-positive inflammatory type 3 dendritic cells triggers preclinical autoimmunity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月21日

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  • Grozdan Cvijetic,
  • Valentina Ottaviani,
  • Isabella O. Conway,
  • Erfan Jabari,
  • Mladen Mitrovic,
  • Haiting Wang,
  • Patrick Fernandes Rodrigues,
  • Anastasia du Halgouet,
  • Siqi Zhao,
  • Harrison C. Wang,
  • Anjali P. Chandroth,
  • Robert J. Palmer Jr.,
  • Eduard Ansaldo,
  • Andrew D. Doyle,
  • Daniel Martin,
  • Roman Szabo,
  • Cristina Corsino,
  • Francesca Pala,
  • Miriam R. Fernandes,
  • Nicolas Bouladoux,
  • Howard A. Young,
  • Yufan Zheng,
  • Zhaoyuan Liu,
  • Florent Ginhoux,
  • Eric V. Dang,
  • Stephen Darnell,
  • George Liechti,
  • Michail S. Lionakis,
  • Robert Ivanek,
  • Luigi D. Notarangelo,
  • Yasmine Belkaid,
  • WanJun Chen,
  • Amiran Dzutsev,
  • Giorgio Trinchieri,
  • Roxane Tussiwand

摘要

Conventional dendritic cells (cDCs) are key sentinels at epithelial barriers, regulating immunity to microbial pathogens and commensals while preserving tissue integrity. NOTCH2 deficiency in CD11c-expressing cells (Notch2cKO) disrupts type 2a DC (cDC2a) development, impairs intestinal TH17 immunity and increases susceptibility to enteropathogenic bacteria. This defect leads to persistent dysbiosis in Notch2cKO mice, characterized by low-grade inflammation and systemic autoimmune features, including elevated autoantibody titers and renal immune complex deposition. Dysbiosis precedes expansion of highly inflammatory AXL-expressing type 3 DCs (AXL+inf-DC3), promoting chronic inflammation and tertiary lymphoid structures driving adaptive immune responses. Notably, dysbiosis is defined by three dominant pathobionts and is transferable to wild-type mice, recapitulating the autoimmune features observed in Notch2cKO mice. Here these findings identify a microbiota–DC axis linking intestinal pathobionts to systemic autoimmunity, establishing inflammatory DC3 as the cellular bridge between dysbiosis, chronic inflammation and autoimmune pathogenesis.