| First Author | Masle-Farquhar E | Year | 2022 |
| Journal | Immunity | Volume | 55 |
| Issue | 12 | Pages | 2386-2404.e8 |
| PubMed ID | 36446385 | Mgi Jnum | J:340910 |
| Mgi Id | MGI:7413819 | Doi | 10.1016/j.immuni.2022.11.001 |
| Citation | Masle-Farquhar E, et al. (2022) STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2D(hi) CD8(+) T cell dysregulation and accumulation. Immunity 55(12):2386-2404.e8 |
| abstractText | 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-gamma, 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. |
