Non-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development

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 and Peter A. Nigrovic ()
Additional contact information
Taehyeung Kim: Harvard Medical School
Marta Martínez-Bonet: Inflammation, and Immunity, Brigham and Women’s Hospital, Harvard Medical School
Qiang Wang: Harvard Medical School
Nicolaj Hackert: Harvard Medical School
Jeffrey A. Sparks: Inflammation, and Immunity, Brigham and Women’s Hospital, Harvard Medical School
Yuriy Baglaenko: Inflammation, and Immunity, Brigham and Women’s Hospital, Harvard Medical School
Byunghee Koh: Inflammation, and Immunity, Brigham and Women’s Hospital, Harvard Medical School
Roxane Darbousset: Harvard Medical School
Raquel Laza-Briviesca: Harvard Medical School
Xiaoting Chen: Cincinnati Children’s Medical Center
Vitor R. C. Aguiar: Harvard Medical School
Darren J. Chiu: Inflammation, and Immunity, Brigham and Women’s Hospital, Harvard Medical School
Harm-Jan Westra: Inflammation, and Immunity, Brigham and Women’s Hospital, Harvard Medical School
Maria Gutierrez-Arcelus: Harvard Medical School
Matthew T. Weirauch: Cincinnati Children’s Medical Center
Soumya Raychaudhuri: Inflammation, and Immunity, Brigham and Women’s Hospital, Harvard Medical School
Deepak A. Rao: Inflammation, and Immunity, Brigham and Women’s Hospital, Harvard Medical School
Peter A. Nigrovic: Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Fine-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.

Date: 2024
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DOI: 10.1038/s41467-024-46457-8

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