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; Original Article; Phosphorylation; Protein Binding

Over the last decades, organ transplantation has made rapid progress as a curative therapy for organ failure. However, the adaptive immune system—alloreactive T cells and antibodies targeting human leukocyte antigens (HLA)—is the leading cause of graft rejection. The presence of anti-donor HLA antibodies is considered a risk factor that disqualifies a particular donor-recipient pair. However, alloantibodies are found in some long-term graft survivors, suggesting a protective blocking function of some alloantibodies. Therefore, whether alloantibodies can have a positive as well as a negative effect in transplantation remains unclear. Here, HLA-A*11:01-specific monoclonal antibodies were generated from a human non-immune antibody library, and the effect of these antibodies was investigated on activation of A*11:01- specific T cells. We identified an A*11:01-specific monoclonal antibody with the capacity to block TCR recognition, TCR recruitment to the immune synapse, and T cell activation. The antibody reduced translocation of the transcription factor NFAT1 and phosphorylation of the MAP kinase ERK, which are both required for T cell effector function and TCR signal transduction. Cross-linking mass spectrometry was used to identify the epitope, demonstrating that this alloantibody can inhibit TCR from binding to the HLA molecule. These findings indicate that some HLA-specific alloantibodies can reduce T cell responses to the allograft. This has significant implications for interpretation of the existence of donor-specific antibodies, since some of them can protect the graft. Moreover, such antibodies may have therapeutic potential as specific treatments targeting mismatched donor HLA molecules. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-025-05614-y.