The immunoglobulin superfamily ligand B7H6 subjects T cell responses to NK cell surveillance

• Published in: Science immunology 2024-05, Vol.9 (95), p.eadj7970-eadj7970
• Main Authors: Kilian, Michael, Friedrich, Mirco J, Lu, Kevin Hai-Ning, Vonhören, David, Jansky, Selina, Michel, Julius, Keib, Anna, Stange, Saskia, Hackert, Nicolaj, Kehl, Niklas, Hahn, Markus, Habel, Antje, Jung, Stefanie, Jähne, Kristine, Sahm, Felix, Betge, Johannes, Cerwenka, Adelheid, Westermann, Frank, Dreger, Peter, Raab, Marc S, Meindl-Beinker, Nadja M, Ebert, Matthias, Bunse, Lukas, Müller-Tidow, Carsten, Schmitt, Michael, Platten, Michael
• Format: Article
• Language: English
• Subjects: Animals; B7 Antigens - immunology; Esophageal Neoplasms - immunology; Female; Humans; Killer Cells, Natural - immunology; Lymphocyte Activation - immunology; Mice; Natural Cytotoxicity Triggering Receptor 3 - immunology; T-Lymphocytes - immunology
• ISSN: 2470-9468; 2470-9468
• DOI: 10.1126/sciimmunol.adj7970

Understanding the mechanisms that regulate T cell immunity is critical for the development of effective therapies for diseases associated with T cell dysfunction, including autoimmune diseases, chronic infections, and cancer. Co-inhibitory "checkpoint molecules," such as programmed cell death protein-1, balance excessive or prolonged immune activation by T cell-intrinsic signaling. Here, by screening for mediators of natural killer (NK) cell recognition on T cells, we identified the immunoglobulin superfamily ligand B7H6 to be highly expressed by activated T cells, including patient-infused CD19-targeting chimeric antigen receptor (CAR) T cells. Unlike other checkpoint molecules, B7H6 mediated NKp30-dependent recognition and subsequent cytolysis of activated T cells by NK cells. B7H6 T cells were prevalent in the tissue and blood of several diseases, and their abundance in tumor tissue positively correlated with clinical response in a cohort of patients with immune checkpoint inhibitor-treated esophageal cancer. In humanized mouse models, NK cell surveillance via B7H6 limited the persistence and antitumor activity of CAR T cells, and its genetic deletion enhanced T cell proliferation and persistence. Together, we provide evidence of B7H6 protein expression by activated T cells and suggest the B7H6-NKp30 axis as a therapeutically actionable NK cell-dependent immune checkpoint that regulates human T cell function.