STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2Dhi CD8+ T cell dysregulation and accumulation
: Masle-Farquhar Etienne, Jackson Katherine JL, 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 RJ, Mustjoki Satu, Brothers Shannon, Vogel Tiphanie P, Brink Robert, Tangye Stuart G, Reed Joanne H, Goodnow Christopher C
Publisher: Elsevier
: 2022
: Immunity
: Immunity
: Immunity
: 55
: 12
: 2386
: 2404.e8
: 1074-7613
: 1097-4180
DOI: https://doi.org/10.1016/j.immuni.2022.11.001
: https://doi.org/10.1016/j.immuni.2022.11.001
: https://research.utu.fi/converis/portal/detail/Publication/177723346
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.
