小柯机器人

澳大利亚达林赫斯特加文医学研究所Christopher C. Goodnow和Etienne Masle-Farquhar共同合作，近期取得重要工作进展。他们研究发现STAT3功能获得性突变通过病理性NKG2D^hi CD8⁺ T细胞失调和积累将白血病与自身免疫性疾病联系起来。相关论文于2022年11月28日在线发表于《免疫》杂志上。

据介绍，癌症与自身免疫性疾病之间的联系无法解释，例如T细胞大颗粒淋巴细胞白血病（T-LGL），其中功能获得（GOF）体细胞STAT3突变与共同存在的自身免疫相关。

为了研究这些突变是否是CD8⁺ T细胞克隆扩增和自身免疫的原因或后果，研究人员分析了具有种系STAT3 GOF突变的患者和小鼠。STAT3 GOF突变驱动了高表达NKG2D（应激诱导MHC I类相关分子的受体）的效应CD8⁺ T细胞克隆的积累。该亚群还表达了颗粒酶、穿孔素、干扰素-γ和Cc15/Rantes基因，并需要NKG2D和IL-15/IL-2受体IL2RB才能进行最大程度的积累。白细胞限制性STAT3 GOF是足够的，CD8⁺ T细胞对于小鼠的致死病理是必不可少的。

结果表明，STAT3 GOF突变导致效应CD8⁺ T细胞寡克隆积累，这些“无赖”细胞导致自身免疫病理，支持白血病/淋巴瘤驱动基因中的体细胞突变导致自身免疫疾病的假设。

附：英文原文

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

Author: 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 Preece, Leena Kainulainen, Michael O’Sullivan, Megan A. Cooper, Mikko R.J. Seppnen, Satu Mustjoki, Shannon Brothers, Tiphanie P. Vogel, Robert Brink, Stuart G. Tangye, Joanne H. Reed, Christopher C. Goodnow

Issue&Volume: 2022-11-28

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.

DOI: 10.1016/j.immuni.2022.11.001

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00591-X

Immunity：《免疫》，创刊于1994年。隶属于细胞出版社，最新IF：43.474
官方网址：https://www.cell.com/immunity/home
投稿链接：https://www.editorialmanager.com/immunity/default.aspx