TY - JOUR
T1 - STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2Dhi CD8+ T cell dysregulation and accumulation
AU - Masle-Farquhar, Etienne
AU - Jackson, Katherine J.L.
AU - Peters, Timothy J.
AU - Al-Eryani, Ghamdan
AU - Singh, Mandeep
AU - Payne, Kathryn J.
AU - Rao, Geetha
AU - Avery, Danielle T.
AU - Apps, Gabrielle
AU - Kingham, Jennifer
AU - Jara, Christopher J.
AU - Skvortsova, Ksenia
AU - Swarbrick, Alexander
AU - Ma, Cindy S.
AU - Suan, Daniel
AU - Uzel, Gulbu
AU - Chua, Ignatius
AU - Leiding, Jennifer W.
AU - Heiskanen, Kaarina
AU - Preece, Kahn
AU - Kainulainen, Leena
AU - O'Sullivan, Michael
AU - Cooper, Megan A.
AU - Seppänen, Mikko R.J.
AU - Mustjoki, Satu
AU - Brothers, Shannon
AU - Vogel, Tiphanie P.
AU - Brink, Robert
AU - Tangye, Stuart G.
AU - Reed, Joanne H.
AU - Goodnow, Christopher C.
N1 - Funding Information:
We thank the patients and their families. We thank Garvan GWCCG, BTF for technical services. This work was supported by NHMRC Program (1113904 to C.C.G.) and Fellowship (1081858 to C.C.G.) grants and by The Bill and Patricia Ritchie Foundation. E.M.−F. designed and performed the majority of experiments; R.B. generated Stat3-mutant mice; K.P. and G.R. performed flow cytometry on PBMCs; C.S.M. D.S. G.U. I.C. J.W.L. K.H. K.P. L.K. M.O. M.A.C. M.R.J.S. S.M. S.B. and S.G.T obtained patient peripheral blood samples; M.S. and G.A. contributed to deep sequencing or single-cell multi-omics; G.A. K.J.L.J. and T.J.P performed bioinformatics analyses; E.M.−F. S.G.T. J.H.R. and C.C.G interpreted experiments and wrote the manuscript. The authors declare no competing interests.
Funding Information:
We thank the patients and their families. We thank Garvan GWCCG, BTF for technical services. This work was supported by NHMRC Program ( 1113904 to C.C.G.) and Fellowship ( 1081858 to C.C.G.) grants and by The Bill and Patricia Ritchie Foundation .
Publisher Copyright:
© 2022 The Authors
PY - 2022/12/13
Y1 - 2022/12/13
N2 - 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.
AB - 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.
KW - CD8 T cells
KW - IL-15
KW - NK-like
KW - NKG2D
KW - STAT3
KW - autoimmune disease
KW - cytokine
KW - danger signals
KW - gain-of-function mutation
KW - leukemia
UR - http://www.scopus.com/inward/record.url?scp=85143711415&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2022.11.001
DO - 10.1016/j.immuni.2022.11.001
M3 - Article
C2 - 36446385
AN - SCOPUS:85143711415
SN - 1074-7613
VL - 55
SP - 2386-2404.e8
JO - Immunity
JF - Immunity
IS - 12
ER -