Functional and Structural Characteristics of HLA-B*13:01-Mediated Specific T Cells Reaction in Dapsone-Induced Drug Hypersensitivity

Abstract

Severe cutaneous adverse drug reactions (SCARs) are a group of serious clinical conditions caused by immune reaction to certain drugs. The allelic variance of human leukocyte antigens of HLA-B*13:01 has been strongly associated with hypersensitivities induced by dapsone (DDS). T-cell receptor mediated activation of cytotoxic T lymphocytes (CTLs) has also been suggested to play an essential role in pathogenesis of SCARs. To investigate the molecular mechanisms for HLA-B*13:01 in the pathogenesis of DDS-induced drug hypersensitivity (DIHS), we performed extra-protein crystallization and expanded drug-specific CTLs to analyze the pathological role of DIHS. Results showed the crystal structure of HLA-B*13:01-beta-2-microglobulin (β2M) complex at 1.5 Å resolution and performed mutation assays demonstrating that I118 or I119, and R121 of HLA-B*13:01 were the key residues that mediate the binding of DDS. Subsequent single-cell TCR and RNA sequencing indicated that TCRs composed of paired TRAV12-3/TRBV28 clonotype with shared CDR3 region specifically recognize HLA-B*13:01-DDS complex to trigger inflammatory cytokines associated with DIHS. We identified the novel p-i-HLA/TCR as the model of interaction between HLA-B*13:01, DDS and the clonotype-specific TCR in DIHS.

Keywords: dapsone, dapsone-induced hypersensitivity syndrome, HLA-B*13:01, T-cell receptor