Perforin expression was neither correlated with clinical and biological markers of disease severity nor predictive of death. The frequency of perforin-positive T4 cells and T8 cells was higher in patients than in HCs (9.9 ± 10.1% versus 4.6 ± 6.4%, p = 0.006 and 46.7 ± 20.6% vs 33.3 ± 18.8%, p = 0.004, respectively). The levels of 15 cytokines in plasma were measured by Luminex. Amounts of intracellular perforin and granzyme-B, as well as cell surface expression of the degranulation marker CD107A were determined by flow cytometry. We recruited 54 volunteers confirmed as being SARS-CoV-2-infected by RT-PCR and admitted to Intensive Care Units (ICUs) or non-ICU, and 29 age- and sex-matched healthy controls (HCs). We therefore measured the expression of perforin, a cytotoxic mediator, in T cells of patients recently hospitalized for SARS-CoV-2 infection. Anti-SARS-CoV-2 immunity may determine acute disease severity, but also the potential persistence of symptoms (long COVID). T cell cytotoxicity plays a major role in antiviral immunity. 11Québec University Hospital, CHU de Québec, Laval University Research Center, Quebec City, QC, Canada.10Pediatrics Department, Nîmes University Hospital, Nîmes, France.9Infectious diseases Department, Nîmes University Hospital, Nîmes, France.8Gerontology Department, Nîmes University Hospital, Nîmes, France.7Medical and Surgical Emergency Department, Nîmes University Hospital, Nîmes, France.6Surgical Intensive Care Department, Nîmes University Hospital, Nîmes, France.5Immunology Department, Montpellier University Hospital, Montpellier, France.4Institute for Regenerative Medicine & Biotherapy, Montpellier University Hospital, Montpellier, France.3Institut National de la Santé et de la Recherche Médicale (INSERM) U1124, Université Paris Cité, Paris, France.2Immunology Department, Nîmes University Hospital, Nîmes, France.1Institute of Human Genetics, Unité Mixte de Recherche 9002 (UMR9002), Centre National de Recherche Scientifique (CNRS) and Montpellier University, Montpellier, France.We conclude that GrB disables Notch1 function, probably resulting in anti-cellular proliferation and cell death signals.Lucy Kundura 1* Renaud Cezar 2 Sonia André 3 Mauricio Campos-Mora 4 Claire Lozano 5 Thierry Vincent 5 Laurent Muller 6 Jean-Yves Lefrant 6 Claire Roger 6 Pierre-Géraud Claret 7 Sandra Duvnjak 8 Paul Loubet 9 Albert Sotto 9 Tu-Ahn Tran 10 Jérôme Estaquier 3,11† Pierre Corbeau 1,2† Overall, cleavage of Notch1 by GrB resulted in a loss of transcriptional activity, independent of Notch1 activation. GrB also displayed perforin-independent functions by cleaving the extracellular domain of Notch1. GrB cleavage of Notch1 can occur in all subcellular compartments, during maturation of the receptor, at the membrane, and in the nucleus. We demonstrate that GrB cleaved the intracellular Notch1 domain at least twice at two distinct aspartic acids, Asp 1860 and Asp 1961. In the present study, we confirmed that Notch1 is a direct and caspase-independent substrate of GrB. ![]() The GrB cleavage sites in Notch1 and functional consequences of Notch1 cleavage by GrB were unknown. A caspase-independent substrate of GrB is the highly conserved transmembrane receptor Notch1. A major player in this process is GrB (granzyme B), which triggers apoptosis in both caspase-dependent and caspase-independent pathways. Granzyme-mediated cell death is the main pathway for cytotoxic lymphocytes to kill virus-infected and tumour cells.
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