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

• 成果类型: Article
• 署名作者: Gong, Meijiao; Myster, Francoise; Azouz, Abdulkader; Sanchez, Guillem Sanchez; Li, Shifang; Charloteaux, Benoit; Yang, Bin; Nichols, Jenna; Lefevre, Lucas; Javaux, Justine; Leemans, Sylvain; Nivelles, Olivier; van Campe, Willem; Roels, Stefan; Mostin, Laurent; van den Berg, Thierry; Davison, Andrew J.; Gillet, Laurent; Connelley, Timothy; Vermijlen, David; Goriely, Stanislas; Vanderplasschen, Alain; Dewals, Benjamin G.
• 署名单位: University of Liege; Universite Libre de Bruxelles; Universite Libre de Bruxelles; WELBIO; University of Liege; University of Glasgow; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); Roslin Institute; University of Edinburgh; Sciensano
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13921
• DOI: 10.1073/pnas.2404536121
• 发表日期: 2024-08-06
• 关键词: malignant catarrhal fever; alcelaphine herpesvirus-1; east-africa; blue wildebeest; receptor; gene; lymphoproliferation; induction; regulator; infection

摘要

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 gamma- herpesvirus- induced PTCL- like disease and identify an essential mechanism explaining its development.