Binding of β₂-glycoprotein I to anionic phospholipids facilitates processing and presentation of a cryptic epitope that activates pathogenic autoreactive T cells

Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder in association with autoantibodies to phospholipid (PL)-binding plasms proteins, such as β₂-glycoprotein I (β₂GPI). We have recently found that CD4⁺ T cells autoreactive to β ₂GPI in patients with APS preferentially recognize a cryptic peptide encompassing amino acid residues 276-290 (p276-290), which contains the major PL-binding site, in the context of DR53. However, it is not clear how previously cryptic p276-290 becomes visible to the immune system and elicits a pathogenics autoimmune response to β₂GPI. Here we show that presentation of a disease-relevant cryptic T-cell determinant in β₂GPI is induced as a direct consequence of antigen processing from β₂GPI bound to anionic PL. Dendritic cells or macrophages pulsed with PL-bound β₂GPI induced a response of p276-290-specific CD4⁺ T-cell lines generated from the patients in an HLA-DR-restricted and antigen-processing-dependent manner but those with β₂GPI or PL alone did not. In addition, the p276-290-reactive T-cell response was primed by stimulating peripheral blood T cells from DR53-carrying healthy individuals with dendritic cells bearing PL-bound β₂GPI in vitro. Our finding is the first demonstration of an in vitro mechanism eliciting pathogenic autoreactive T-cell responses to β₂GPI and should be useful in clarifying the pathogenesis of APS.