Non-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development
Abstrak
AbstractFine-mapping and functional studies implicate rs117701653, a non-coding single nucleotide polymorphism in the CD28/CTLA4/ICOS locus, as a risk variant for rheumatoid arthritis and type 1 diabetes. Here, using DNA pulldown, mass spectrometry, genome editing and eQTL analysis, we establish that the disease-associated risk allele is functional, reducing affinity for the inhibitory chromosomal regulator SMCHD1 to enhance expression of inducible T-cell costimulator (ICOS) in memory CD4+ T cells from healthy donors. Higher ICOS expression is paralleled by an increase in circulating T peripheral helper (Tph) cells and, in rheumatoid arthritis patients, of blood and joint fluid Tph cells as well as circulating plasmablasts. Correspondingly, ICOS ligation and carriage of the rs117701653 risk allele accelerate T cell differentiation into CXCR5-PD-1high Tph cells producing IL-21 and CXCL13. Thus, mechanistic dissection of a functional non-coding variant in human autoimmunity discloses a previously undefined pathway through which ICOS regulates Tph development and abundance.
Penulis (18)
Taehyeung Kim
Marta Martínez-Bonet
Qiang Wang
Nicolaj Hackert
Jeffrey A. Sparks
Yuriy Baglaenko
Byunghee Koh
Roxane Darbousset
Raquel Laza-Briviesca
Xiaoting Chen
Vitor R. C. Aguiar
Darren J. Chiu
Harm-Jan Westra
Maria Gutierrez-Arcelus
Matthew T. Weirauch
Soumya Raychaudhuri
Deepak A. Rao
Peter A. Nigrovic
Akses Cepat
- Tahun Terbit
- 2024
- Bahasa
- en
- Total Sitasi
- 9×
- Sumber Database
- CrossRef
- DOI
- 10.1038/s41467-024-46457-8
- Akses
- Open Access ✓