Journal Article

Occlusion of TCR binding to HLA-A11:01 by a non-pathogenic human alloantibody

Gascoigne, Nicholas R. J., Sobota, Radoslaw M., Brzostek, Joanna, Yap, Jiawei, Vathsala, Anantharaman, Tay, Neil Q., Chua, Yen Leong, MacAry, Paul A., Lim, Yan Ting, Gu, Yue, Ser, Zheng, Wood, Kathryn J., Hamidinia, Maryam

2025

Overview

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

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: Adaptive systems / Alloantibodies / allografting / Animals / Antibodies / Antibodies, Monoclonal - immunology / Antibody libraries / Binding / Biochemistry / Biomedical and Life Sciences / Biomedicine / Blocking / Cell activation / Cell Biology / Crosslinking / Epitopes / Graft rejection / Graft Rejection - immunology / Grafting / Histocompatibility antigen HLA / HLA-A11 Antigen - immunology / HLA-A11 Antigen - metabolism / Humans / Immune system / Isoantibodies - immunology / Kinases / Life Sciences / Lymphocyte Activation - immunology / Lymphocytes / Lymphocytes T / MAP kinase / Mass spectrometry / Mass spectroscopy / mitogen-activated protein kinase / Monoclonal antibodies / NF-AT1 protein / NFATC Transcription Factors - metabolism / Occlusion / organ transplantation / Original / Original Article / Phosphorylation / Protein Binding / Receptors, Antigen, T-Cell - immunology / Receptors, Antigen, T-Cell - metabolism / Risk factors / Signal transduction / synapse / T cell receptors / T-lymphocytes / T-Lymphocytes - immunology / transcription factors / Translocation / Transplantation