STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2Dhi CD8+ T cell dysregulation and accumulation

Etienne Masle-Farquhar, Katherine J.L. Jackson, Timothy J. Peters, Ghamdan Al-Eryani, Mandeep Singh, Kathryn J. Payne, Geetha Rao, Danielle T. Avery, Gabrielle Apps, Jennifer Kingham, Christopher J. Jara, Ksenia Skvortsova, Alexander Swarbrick, Cindy S. Ma, Daniel Suan, Gulbu Uzel, Ignatius Chua, Jennifer W. Leiding, Kaarina Heiskanen, Kahn PreeceLeena Kainulainen, Michael O'Sullivan, Megan A. Cooper, Mikko R.J. Seppänen, Satu Mustjoki, Shannon Brothers, Tiphanie P. Vogel, Robert Brink, Stuart G. Tangye, Joanne H. Reed, Christopher C. Goodnow

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish
Pages (from-to)2386-2404.e8
JournalImmunity
Volume55
Issue number12
DOIs
StatePublished - Dec 13 2022

Keywords

  • CD8 T cells
  • IL-15
  • NK-like
  • NKG2D
  • STAT3
  • autoimmune disease
  • cytokine
  • danger signals
  • gain-of-function mutation
  • leukemia

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