DECTIN-1: A modifier protein in CTLA-4 haploinsufficiency.

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Autosomal dominant loss-of-function variants in CTLA4 cause immune dysregulation, autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL).
• IDAIL exhibits incomplete penetrance and variable expressivity, suggesting the involvement of genetic modifiers.
• CTLA-4 haploinsufficiency (CTLA-4h) is a key factor in IDAIL pathogenesis.

Purpose of the Study:

• To investigate the role of genetic modifiers in CTLA-4 haploinsufficiency.
• To identify novel genes that influence the expressivity of CTLA4 variants.
• To elucidate the functional interaction between CTLA4 and potential modifier genes in immune homeostasis.

Main Methods:

• Case study of an IDAIL proband with compound heterozygous variants in CTLA4 and CLEC7A.
• Functional analysis of the CLEC7A variant to assess DECTIN-1 dimerization and surface expression.
• In vitro studies on regulatory T cell (Treg) differentiation upon DECTIN-1 stimulation.
• Assessment of Treg defects in the context of partial DECTIN-1 deficiency and CTLA-4 haploinsufficiency.

Main Results:

• The proband carried pathogenic CTLA4 and rare CLEC7A loss-of-function variants.
• The CLEC7A variant abrogated DECTIN-1 dimerization and surface expression.
• DECTIN-1 stimulation promoted Treg differentiation independently of TGF-β.
• Partial DECTIN-1 deficiency exacerbated CTLA-4h-associated Treg defects.

Conclusions:

• CLEC7A acts as a genetic modifier in CTLA-4 haploinsufficiency.
• DECTIN-1 signaling modulates regulatory T cell function and immune homeostasis.
• Functional epistasis between CTLA4 and CLEC7A influences the expressivity of immune dysregulation.