Details

Autor(en) / Beteiligte

• Bhuyan, Zaied Ahmed
• Rahman, M. Arifur
• Maradana, Muralidhara Rao
• Mehdi, Ahmed M.
• Bergot, Anne-Sophie
• Simone, Davide
• El-Kurdi, Marya
• Garrido-Mesa, Jose
• Cai, Cheng Bang Benjamin
• Cameron, Amy J.
• Hanson, Aimee L.
• Nel, Hendrik J.
• Kenna, Tony
• Leo, Paul
• Rehaume, Linda
• Brown, Matthew A.
• Ciccia, Francesco
• Thomas, Ranjeny

Titel

Genetically encoded Runx3 and CD4+ intestinal epithelial lymphocyte deficiencies link SKG mouse and human predisposition to spondyloarthropathy

Ist Teil von

• Clinical immunology (Orlando, Fla.), 2023-02, Vol.247, p.109220-109220, Article 109220

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• Disturbances in immune regulation, intestinal dysbiosis and inflammation characterize ankylosing spondylitis (AS), which is associated with RUNX3 loss-of-function variants. ZAP70W163C mutant (SKG) mice have reduced ZAP70 signaling, spondyloarthritis and ileitis. In small intestine, Foxp3+ regulatory T cells (Treg) and CD4+CD8αα+TCRαβ+ intraepithelial lymphocytes (CD4-IEL) control inflammation. TGF-β and retinoic acid (RA)-producing dendritic cells and MHC-class II+ intestinal epithelial cells (IEC) are required for Treg and CD4-IEL differentiation from CD4+ conventional or Treg precursors, with upregulation of Runx3 and suppression of ThPOK. We show in SKG mouse ileum, that ZAP70W163C or ZAP70 inhibition prevented CD4-IEL but not Treg differentiation, dysregulating Runx3 and ThPOK. TGF-β/RA-mediated CD4-IEL development, T-cell IFN-γ production, MHC class-II+ IEC, tissue-resident memory T-cell and Runx3-regulated genes were reduced. In AS intestine, CD4-IEL were decreased, while in AS blood CD4+CD8+ T cells were reduced and Treg increased. Thus, genetically-encoded TCR signaling dysfunction links intestinal T-cell immunodeficiency in mouse and human spondyloarthropathy.