Occlusion of TCR binding to HLA-A*11:01 by a non-pathogenic human alloantibody

• DOI: 10.1007/s00018-025-05614-y
• Publication Date: 2025-02-26T07:51:14Z
• Authors: Maryam Hamidinia; Yue Gu; Zheng Ser; Joanna Brzostek; Neil Q. Tay; Jiawei Yap; Yen Leong Chua; Yan Ting Lim; Kathryn J. Wood; Anantharaman Vath...; Radoslaw M. Sobota; Paul A. MacAry; Nicholas R. J. Ga...
• Keywords: Transplantation; Alloantibody; Human antibody; NFATC Transcription Factors; Donor-specific antibodies (DSA); T-Lymphocytes; T-Cell; Lymphocyte Activation; Antibodies; HLA-A11 Antigen; Cross-linking mass spectrometry (XL-MS); Isoantibodies; Antigen; Receptors; Monoclonal; Humans; Animals; Phosphorylation; Protein Binding

Over the last decades, organ transplantation has made rapid progress as a curative therapy for failure. However, adaptive immune system—alloreactive T cells and antibodies targeting human leukocyte antigens (HLA)—is leading cause of graft rejection. The presence anti-donor HLA is considered risk factor that disqualifies particular donor-recipient pair. alloantibodies are found in some long-term survivors, suggesting protective blocking function alloantibodies. Therefore, whether can have positive well negative effect remains unclear. Here, HLA-A*11:01-specific monoclonal were generated from non-immune antibody library, these was investigated on activation A*11:01- specific cells. We identified an A*11:01-specific with capacity to block TCR recognition, recruitment synapse, cell activation. reduced translocation transcription NFAT1 phosphorylation MAP kinase ERK, which both required effector signal transduction. Cross-linking mass spectrometry used identify epitope, demonstrating this alloantibody inhibit binding molecule. These findings indicate HLA-specific reduce responses allograft. This significant implications interpretation existence donor-specific antibodies, since them protect graft. Moreover, such may therapeutic potential treatments mismatched donor molecules.