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STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2Dhi CD8+ T cell dysregulation and accumulation.
Masle-Farquhar, Etienne; Jackson, Katherine J L; Peters, Timothy J; Al-Eryani, Ghamdan; Singh, Mandeep; Payne, Kathryn J; Rao, Geetha; Avery, Danielle T; Apps, Gabrielle; Kingham, Jennifer; Jara, Christopher J; Skvortsova, Ksenia; Swarbrick, Alexander; Ma, Cindy S; Suan, Daniel; Uzel, Gulbu; Chua, Ignatius; Leiding, Jennifer W; Heiskanen, Kaarina; Preece, Kahn; Kainulainen, Leena; O'Sullivan, Michael; Cooper, Megan A; Seppänen, Mikko R J; Mustjoki, Satu; Brothers, Shannon; Vogel, Tiphanie P; Brink, Robert; Tangye, Stuart G; Reed, Joanne H; Goodnow, Christopher C.
Afiliación
  • Masle-Farquhar E; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Sydney, NSW 2052, Australia. Electronic address: e.masle-farquhar@garvan.org.au.
  • Jackson KJL; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
  • Peters TJ; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Al-Eryani G; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Singh M; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Payne KJ; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
  • Rao G; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
  • Avery DT; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
  • Apps G; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; Australian BioResources, Moss Vale, NSW 2577, Australia.
  • Kingham J; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; Australian BioResources, Moss Vale, NSW 2577, Australia.
  • Jara CJ; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Skvortsova K; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Swarbrick A; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Ma CS; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Suan D; Westmead Clinical School, The University of Sydney, Westmead, Sydney, NSW, Australia.
  • Uzel G; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
  • Chua I; Canterbury Health Laboratories, Christchurch, New Zealand.
  • Leiding JW; Division of Allergy and Immunology, Department of Pediatrics, University of South Florida, Tampa, FL, USA; Division of Allergy and Immunology, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
  • Heiskanen K; Children's Immunodeficiency Unit, Hospital for Children and Adolescents, and Pediatric Research Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
  • Preece K; Department of Immunology, John Hunter Children's Hospital, Newcastle, NSW, Australia.
  • Kainulainen L; Department of Pediatrics, Turku University Hospital, University of Turku, Turku, Finland.
  • O'Sullivan M; Immunology Department, Fiona Stanley Hospital, Murdoch, WA, Australia.
  • Cooper MA; Department of Pedatrics, Division of Rheumatology/Immunology, Washington University School of Medicine, St. Louis, MO, USA.
  • Seppänen MRJ; Rare Disease and Pediatric Research Centers, Hospital for Children and Adolescents, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
  • Mustjoki S; Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland; iCAN Digital Precision
  • Brothers S; Starship Children's Hospital, Auckland, New Zealand.
  • Vogel TP; Department of Pedatrics, Division of Rheumatology/Immunology, Washington University School of Medicine, St. Louis, MO, USA.
  • Brink R; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Tangye SG; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Reed JH; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Goodnow CC; The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; Cellular Genomics Futures Institute, UNSW Sydney, Sydney, NSW, Australia. Electronic address: c.goodnow@garvan.org.au.
Immunity ; 55(12): 2386-2404.e8, 2022 12 13.
Article en En | MEDLINE | ID: mdl-36446385
ABSTRACT
The association between cancer and autoimmune disease is unexplained, exemplified by T cell large granular lymphocytic leukemia (T-LGL) where gain-of-function (GOF) somatic STAT3 mutations correlate with co-existing autoimmunity. To investigate whether these mutations are the cause or consequence of CD8+ T cell clonal expansions and autoimmunity, we analyzed patients and mice with germline STAT3 GOF mutations. STAT3 GOF mutations drove the accumulation of effector CD8+ T cell clones highly expressing NKG2D, the receptor for stress-induced MHC-class-I-related molecules. This subset also expressed genes for granzymes, perforin, interferon-γ, and Ccl5/Rantes and required NKG2D and the IL-15/IL-2 receptor IL2RB for maximal accumulation. Leukocyte-restricted STAT3 GOF was sufficient and CD8+ T cells were essential for lethal pathology in mice. These results demonstrate that STAT3 GOF mutations cause effector CD8+ T cell oligoclonal accumulation and that these rogue cells contribute to autoimmune pathology, supporting the hypothesis that somatic mutations in leukemia/lymphoma driver genes contribute to autoimmune disease.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Enfermedades Autoinmunes / Leucemia Linfocítica Granular Grande Límite: Animals Idioma: En Revista: Immunity Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2022 Tipo del documento: Article
Texto completo
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PubMed Links
Buscar en Google

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Enfermedades Autoinmunes / Leucemia Linfocítica Granular Grande Límite: Animals Idioma: En Revista: Immunity Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2022 Tipo del documento: Article