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

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...

Full description

Saved in:
Bibliographic Details
Published in:Clinical immunology (Orlando, Fla.) Fla.), 2023-02, Vol.247, p.109220-109220, Article 109220
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Ankylosing spondylitis
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Core Binding Factor Alpha 3 Subunit - genetics
Humans
Immunodeficiency
Inflammation
Intestinal Mucosa
Intestine
Intestines
Mice
Receptors, Antigen, T-Cell, alpha-beta
Runx3
Spondylarthropathies - genetics
T cells
Transforming Growth Factor beta
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1521-6616
1521-7035
DOI:10.1016/j.clim.2022.109220