CTLA4 rs3087243-A–linked haplotype is associated with increased CTLA-4 expression and suppressive function in human regulatory T cells

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Abstract
CTLA-4 is an inhibitory receptor on T cells that limits immune activation by competing with the co-stimulatory receptor CD28 for binding to CD80 and CD86 on antigen-presenting cells. Regulatory T cells (Tregs) employ CTLA-4–mediated transendocytosis as a key suppressive mechanism. Several CTLA4 polymorphisms are associated with autoimmune disease risk and may modulate CTLA-4 expression and function. Here, we analyzed samples from 155 genotyped subjects using flow cytometry and functional assays to determine how haplotypes formed by 3 CTLA4 single-nucleotide polymorphisms shape T-cell phenotype and function ex vivo. The autoimmune-protective CTLA4 rs5742909-rs231775-rs3087243 CAA haplotype was linked to increased intracellular CTLA-4 expression in both Tregs and conventional CD4+ T cells compared with CGG, CAG, and TAG haplotypes, implicating rs3087243 as the likely causal variant. The CAA haplotype was also associated with increased Treg frequencies. In Tregs from CAA/CAA subjects, elevated steady-state CTLA-4 expression promoted enhanced early CTLA-4 surface mobilization following anti-CD3/anti-CD28 stimulation. Moreover, naïve Tregs from CAA/CAA subjects more effectively suppressed naïve CD4+ T-cell proliferation in the presence of CD80/CD86-expressing dendritic cells. Collectively, these findings indicate that the rs3087243-A–linked CAA haplotype is associated with increased CTLA-4 expression and enhanced Treg function, providing a mechanistic explanation for its protective association with autoimmunity.

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