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

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 protei...

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Main Authors: Kilian, Michael (Author) , Friedrich, Mirco (Author) , Lu, Kevin Hai-Ning (Author) , Vonhören, David (Author) , Jansky, Selina (Author) , Michel, Julius (Author) , Keib, Anna (Author) , Stange, Saskia (Author) , Hackert, Nicolaj (Author) , Kehl, Niklas (Author) , Hahn, Markus (Author) , Habel, Antje (Author) , Jung, Stefanie (Author) , Jähne, Kristine (Author) , Sahm, Felix (Author) , Betge, Johannes (Author) , Cerwenka, Adelheid (Author) , Westermann, Frank (Author) , Dreger, Peter (Author) , Raab, Marc-Steffen (Author) , Meindl-Beinker, Nadja M. (Author) , Ebert, Matthias (Author) , Bunse, Lukas (Author) , Müller-Tidow, Carsten (Author) , Schmitt, Michael (Author) , Platten, Michael (Author)
Format: Article (Journal)
Language:English
Published: 3 May 2024
In: Science immunology
Year: 2024, Volume: 9, Issue: 95
ISSN:2470-9468
DOI:10.1126/sciimmunol.adj7970
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1126/sciimmunol.adj7970
Verlag, lizenzpflichtig, Volltext: https://www.science.org/doi/10.1126/sciimmunol.adj7970
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Author Notes:Michael Kilian, Mirco J. Friedrich, Kevin Hai-Ning Lu, David Vonhören, Selina Jansky, Julius Michel, Anna Keib, Saskia Stange, Nicolaj Hackert, Niklas Kehl, Markus Hahn, Antje Habel, Stefanie Jung, Kristine Jähne, Felix Sahm, Johannes Betge, Adelheid Cerwenka, Frank Westermann, Peter Dreger, Marc S. Raab, Nadja M. Meindl-Beinker, Matthias Ebert, Lukas Bunse, Carsten Müller-Tidow, Michael Schmitt, Michael Platten
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Summary: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.
Item Description:Gesehen am 11.12.2024
Physical Description:Online Resource
ISSN:2470-9468
DOI:10.1126/sciimmunol.adj7970

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