| Title: |
STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2Dhi CD8+T cell dysregulation and accumulation |
| Authors: |
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. |
| Contributors: |
HUS Children and Adolescents; University of Helsinki; Children's Hospital; Clinicum; HUS Comprehensive Cancer Center; Department of Clinical Chemistry and Hematology; Hematologian yksikkö; TRIMM - Translational Immunology Research Program; Digital Precision Cancer Medicine (iCAN) |
| Publisher Information: |
Cell Press |
| Publication Year: |
2023 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
Cd8(+) t-cells; Nk cells; Selective stimulation; Killer-cells; Mic ligands; In-vivo; Expression; Receptor; Transcription; Pathogenesis; General medicine; internal medicine and other clinical medicine |
| Description: |
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 -exist-ing 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-y, and Ccl5/Rantes and required NKG2D and the IL-15/IL-2 receptor IL2RB for maximal accumula-tion. 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 accumu-lation and that these rogue cells contribute to autoimmune pathology, supporting the hypothesis that somatic mutations in leukemia/lymphoma driver genes contribute to autoimmune disease. ; Peer reviewed |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://hdl.handle.net/10138/354048; 000913418400001 |
| Availability: |
https://hdl.handle.net/10138/354048 |
| Rights: |
cc_by_nc_nd ; info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.C1498A12 |
| Database: |
BASE |