Unraveling clonal CD8 T cell expansion and identification of essential factors in γ-herpesvirus-induced lymphomagenesis.

Autor:	Gong M; Department of Infectious and Parasitic Diseases, Faculty of Veterinary Medicine-Fundamental and Applied Research for Animals & Health (FARAH), University of Liège, Liège 4000, Belgium., Myster F; Department of Infectious and Parasitic Diseases, Faculty of Veterinary Medicine-Fundamental and Applied Research for Animals & Health (FARAH), University of Liège, Liège 4000, Belgium., Azouz A; Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies 6041, Belgium.; Center for Research in Immunology, Université Libre de Bruxelles, Gosselies 6041, Belgium., Sanchez Sanchez G; Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies 6041, Belgium.; Center for Research in Immunology, Université Libre de Bruxelles, Gosselies 6041, Belgium.; Department of Pharmacotherapy and Pharmaceutics, Université Libre de Bruxelles, Brussels 1050, Belgium.; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), WEL Research Institute, Wavre 1300, Belgium., Li S; Department of Infectious and Parasitic Diseases, Faculty of Veterinary Medicine-Fundamental and Applied Research for Animals & Health (FARAH), University of Liège, Liège 4000, Belgium., Charloteaux B; Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), GIGA-Genomics core facility, University of Liège, Liège 4000, Belgium., Yang B; Department of Infectious and Parasitic Diseases, Faculty of Veterinary Medicine-Fundamental and Applied Research for Animals & Health (FARAH), University of Liège, Liège 4000, Belgium., Nichols J; Medical Research Council (MRC)-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, United Kingdom., Lefevre L; The Roslin Institute, The Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, United Kingdom., Javaux J; Department of Infectious and Parasitic Diseases, Faculty of Veterinary Medicine-Fundamental and Applied Research for Animals & Health (FARAH), University of Liège, Liège 4000, Belgium., Leemans S; Department of Infectious and Parasitic Diseases, Faculty of Veterinary Medicine-Fundamental and Applied Research for Animals & Health (FARAH), University of Liège, Liège 4000, Belgium., Nivelles O; Department of Infectious and Parasitic Diseases, Faculty of Veterinary Medicine-Fundamental and Applied Research for Animals & Health (FARAH), University of Liège, Liège 4000, Belgium., van Campe W; Sciensano, Scientific Directorate Infectious Diseases in Animals, Experimental Center Machelen, Machelen 1830, Belgium., Roels S; Sciensano, Scientific Directorate Infectious Diseases in Animals, Experimental Center Machelen, Machelen 1830, Belgium., Mostin L; Sciensano, Scientific Directorate Infectious Diseases in Animals, Experimental Center Machelen, Machelen 1830, Belgium., van den Berg T; Sciensano, Scientific Directorate Infectious Diseases in Animals, Experimental Center Machelen, Machelen 1830, Belgium., Davison AJ; Medical Research Council (MRC)-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, United Kingdom., Gillet L; Department of Infectious and Parasitic Diseases, Faculty of Veterinary Medicine-Fundamental and Applied Research for Animals & Health (FARAH), University of Liège, Liège 4000, Belgium., Connelley T; The Roslin Institute, The Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, United Kingdom., Vermijlen D; Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies 6041, Belgium.; Center for Research in Immunology, Université Libre de Bruxelles, Gosselies 6041, Belgium.; Department of Pharmacotherapy and Pharmaceutics, Université Libre de Bruxelles, Brussels 1050, Belgium.; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), WEL Research Institute, Wavre 1300, Belgium., Goriely S; Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies 6041, Belgium.; Center for Research in Immunology, Université Libre de Bruxelles, Gosselies 6041, Belgium., Vanderplasschen A; Department of Infectious and Parasitic Diseases, Faculty of Veterinary Medicine-Fundamental and Applied Research for Animals & Health (FARAH), University of Liège, Liège 4000, Belgium.; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), WEL Research Institute, Wavre 1300, Belgium., Dewals BG; Department of Infectious and Parasitic Diseases, Faculty of Veterinary Medicine-Fundamental and Applied Research for Animals & Health (FARAH), University of Liège, Liège 4000, Belgium.; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), WEL Research Institute, Wavre 1300, Belgium.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Aug 06; Vol. 121 (32), pp. e2404536121. Date of Electronic Publication: 2024 Aug 01.
DOI:	10.1073/pnas.2404536121
Abstrakt:	Alcelaphine gammaherpesvirus 1 (AlHV-1) asymptomatically persists in its natural host, the wildebeest. However, cross-species transmission to cattle results in the induction of an acute and lethal peripheral T cell lymphoma-like disease (PTCL), named malignant catarrhal fever (MCF). Our previous findings demonstrated an essential role for viral genome maintenance in infected CD8 + T lymphocytes but the exact mechanism(s) leading to lymphoproliferation and MCF remained unknown. To decipher how AlHV-1 dysregulates T lymphocytes, we first examined the global phenotypic changes in circulating CD8 + T cells after experimental infection of calves. T cell receptor repertoire together with transcriptomics and epigenomics analyses demonstrated an oligoclonal expansion of infected CD8 + T cells displaying effector and exhaustion gene signatures, including GZMA, GNLY, PD-1, and TOX2 expression. Then, among viral genes expressed in infected CD8 + T cells, we uncovered A10 that encodes a transmembrane signaling protein displaying multiple tyrosine residues, with predicted ITAM and SH3 motifs. Impaired A10 expression did not affect AlHV-1 replication in vitro but rendered AlHV-1 unable to induce MCF. Furthermore, A10 was phosphorylated in T lymphocytes in vitro and affected T cell signaling. Finally, while AlHV-1 mutants expressing mutated forms of A10 devoid of ITAM or SH3 motifs (or both) were able to induce MCF, a recombinant virus expressing a mutated form of A10 unable to phosphorylate its tyrosine residues resulted in the lack of MCF and protected against a wild-type virus challenge. Thus, we could characterize the nature of this γ-herpesvirus-induced PTCL-like disease and identify an essential mechanism explaining its development. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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