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STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2D hi CD8 + T cell dysregulation and accumulation.
- Source :
-
Immunity [Immunity] 2022 Dec 13; Vol. 55 (12), pp. 2386-2404.e8. Date of Electronic Publication: 2022 Nov 28. - Publication Year :
- 2022
-
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 <superscript>+</superscript> 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 <superscript>+</superscript> 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 <superscript>+</superscript> T cells were essential for lethal pathology in mice. These results demonstrate that STAT3 GOF mutations cause effector CD8 <superscript>+</superscript> 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.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Mice
CD8-Positive T-Lymphocytes
Gain of Function Mutation
Mutation
NK Cell Lectin-Like Receptor Subfamily K genetics
STAT3 Transcription Factor genetics
STAT3 Transcription Factor metabolism
Autoimmune Diseases genetics
Autoimmune Diseases pathology
Leukemia, Large Granular Lymphocytic genetics
Leukemia, Large Granular Lymphocytic pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4180
- Volume :
- 55
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Immunity
- Publication Type :
- Academic Journal
- Accession number :
- 36446385
- Full Text :
- https://doi.org/10.1016/j.immuni.2022.11.001