Dysbiosis-induced expansion of AXL-positive inflammatory type 3 dendritic cells triggers preclinical autoimmunity
Abstract
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 ( Notch2 cKO ) disrupts type 2a DC (cDC2a) development, impairs intestinal T H 17 immunity and increases susceptibility to enteropathogenic bacteria. This defect leads to persistent dysbiosis in Notch2 cKO 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 Notch2 cKO 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.
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BibTeX
@article{cvijetic2026dysbiosisinduced,
title = {{Dysbiosis-induced expansion of AXL-positive inflammatory type 3 dendritic cells triggers preclinical autoimmunity}},
author = {Grozdan Cvijetic and Valentina Ottaviani and Isabella Conway and Erfan Jabari and Mladen Mitrovic and Haiting Wang and Patrick Fernandes Rodrigues and Anastasia Du Halgouet and Siqi Zhao and Harrison Wang and Anjali Chandroth and Robert Palmer and Eduard Ansaldo and Andrew Doyle and Daniel Martin and Roman Szabo and Cristina Corsino and Francesca Pala and Miriam Fernandes and Nicolas Bouladoux and Howard Young and Yufan Zheng and Zhaoyuan Liu and Florent Ginhoux and Eric Dang and Stephen Darnell and George Liechti and Michail Lionakis and Robert Ivanek and Luigi Notarangelo and Yasmine Belkaid and Wanjun Chen and Amiran Dzutsev and Giorgio Trinchieri and Roxane Tussiwand},
journal = {Nature Immunology},
year = {2026},
month = jul,
doi = {10.1038/s41590-026-02599-z},
url = {https://pasteur.hal.science/pasteur-05741356v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Dysbiosis-induced expansion of AXL-positive inflammatory type 3 dendritic cells triggers preclinical autoimmunity
AU - Grozdan Cvijetic
AU - Valentina Ottaviani
AU - Isabella Conway
AU - Erfan Jabari
AU - Mladen Mitrovic
AU - Haiting Wang
AU - Patrick Fernandes Rodrigues
AU - Anastasia Du Halgouet
AU - Siqi Zhao
AU - Harrison Wang
AU - Anjali Chandroth
AU - Robert Palmer
AU - Eduard Ansaldo
AU - Andrew Doyle
AU - Daniel Martin
AU - Roman Szabo
AU - Cristina Corsino
AU - Francesca Pala
AU - Miriam Fernandes
AU - Nicolas Bouladoux
AU - Howard Young
AU - Yufan Zheng
AU - Zhaoyuan Liu
AU - Florent Ginhoux
AU - Eric Dang
AU - Stephen Darnell
AU - George Liechti
AU - Michail Lionakis
AU - Robert Ivanek
AU - Luigi Notarangelo
AU - Yasmine Belkaid
AU - Wanjun Chen
AU - Amiran Dzutsev
AU - Giorgio Trinchieri
AU - Roxane Tussiwand
PY - 2026
DA - 2026/07/21
JO - Nature Immunology
DO - 10.1038/s41590-026-02599-z
UR - https://pasteur.hal.science/pasteur-05741356v1
AB - 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 ( Notch2 cKO ) disrupts type 2a DC (cDC2a) development, impairs intestinal T H 17 immunity and increases susceptibility to enteropathogenic bacteria. This defect leads to persistent dysbiosis in Notch2 cKO 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 Notch2 cKO 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.
SN - 1529-2908
SN - 1529-2916
ER -