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

Area of Science:

• Immunology
• Genetics
• Autoimmunity

Background:

• Fine-mapping identified rs117701653, a non-coding SNP in the CD28/CTLA4/ICOS locus, as a risk variant for rheumatoid arthritis (RA) and type 1 diabetes (T1D).
• Understanding the functional impact of non-coding variants is crucial for elucidating autoimmune disease pathogenesis.

Purpose of the Study:

• To functionally characterize the disease-associated risk allele rs117701653.
• To investigate the role of inducible T-cell costimulator (ICOS) in T peripheral helper (Tph) cell development and its contribution to autoimmunity.

Main Methods:

• DNA pulldown assays
• Mass spectrometry
• Genome editing
• Expression quantitative trait loci (eQTL) analysis
• Flow cytometry
• Cytokine profiling

Main Results:

• The risk allele of rs117701653 reduces SMCHD1 binding, enhancing ICOS expression in memory CD4+ T cells.
• Increased ICOS expression correlates with elevated Tph cell populations in healthy donors and RA patients.
• The risk allele promotes T cell differentiation into IL-21 and CXCL13-producing Tph cells.

Conclusions:

• The rs117701653 risk allele is functional and contributes to autoimmunity by modulating ICOS expression.
• ICOS signaling plays a critical role in the development and expansion of pathogenic Tph cells.
• This study reveals a novel ICOS-dependent pathway in Tph cell regulation relevant to human autoimmune diseases.