Activated STING in the thymus alters T cell development and selection leading to autoimmunity.
Activated STING in the thymus alters T cell development and selection leading to autoimmunity.
复制标题
胸腺中激活的 STING 会改变 T 细胞的发育和选择，从而导致自身免疫。
DOI：
10.1101/2024.02.17.580803
复制
发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Shum,AnthonyK
中科院分区：
文献类型：
--
作者：
Deng,Zimu;Law,ChristopherS;Kurra,Santosh;Simchoni,Noa;Shum,AnthonyK
将全身炎症障碍分为自体炎症或自身免疫，有助于了解疾病的发病机制，以及治疗应针对先天分子及其信号通路还是适应性免疫反应。COPA综合征是一种免疫失调的单基因紊乱，导致间质性肺疾病和高滴度自身抗体。研究表明，先天免疫分子刺痛的结构性激活与疾病密切相关。然而，在COPA综合征或更常见的自身免疫性疾病中，叮咬导致T细胞耐受性和自身免疫丧失的机制尚不清楚。使用CopaE241K/+小鼠，我们发现了刺痛在胸腺中的功能作用。人类胸腺的单细胞数据表明，STING在胸腺髓质上皮细胞(MTECs)中高度表达，mTECs参与处理和向胸腺细胞递送自身抗原。在CopaE241K/+小鼠中，mTECs中激活的STING触发了干扰素信号，损害了巨噬细胞的自噬，并导致T细胞阴性选择的缺陷。给予全身刺痛激动剂的野生型小鼠出现了选择缺陷，并显示出针对黑色素瘤中也表达的自身抗原的T细胞克隆的胸腺逃逸增强。我们的工作证明了TECs中的STING激活塑造了T细胞谱系，并有助于自身免疫，这一发现对于激活胸腺STING的设置很重要。
Classifying systemic inflammatory disorders as autoinflammatory or autoimmune provides insight into disease pathogenesis and whether treatment should target innate molecules and their signaling pathways or the adaptive immune response. COPA syndrome is a monogenic disorder of immune dysregulation that leads to interstitial lung disease and high-titer autoantibodies. Studies show constitutive activation of the innate immune molecule STING is centrally involved in disease. However, the mechanisms by which STING results in loss of T cell tolerance and autoimmunity in COPA syndrome or more common autoimmune diseases is not understood. Using CopaE241K/+ mice, we uncovered a functional role for STING in the thymus. Single cell data of human thymus demonstrates STING is highly expressed in medullary thymic epithelial cells (mTECs) involved in processing and presenting self-antigens to thymocytes. In CopaE241K/+ mice, activated STING in mTECs triggered interferon signaling, impaired macroautophagy and caused a defect in negative selection of T cells. Wild-type mice given a systemic STING agonist phenocopied the selection defect and showed enhanced thymic escape of a T cell clone targeting a self-antigen also expressed in melanoma. Our work demonstrates STING activation in TECs shapes the T cell repertoire and contributes to autoimmunity, findings important for settings that activate thymic STING.
登录
查看更多内容
黑素细胞刺激激素的体外生物测定。
影响因子：
4.8
作者：
K. Shizume;A. Lerner;T. Fitzpatrick
通讯作者：
T. Fitzpatrick
铯盐全星化制备Merrifield树脂
DOI：
--
发表时间：
1973
期刊：
影响因子：
--
作者：
B. Gisin
通讯作者：
B. Gisin
鲑鱼黑色素浓缩激素片段和类似物的结构活性研究
影响因子：
3
作者：
B. Baker;R. G. Kinsman;C. Moss;P. D. White;P. Paul;D. W. Brown;M. M. Campbell;D. Osguthorpe
通讯作者：
D. Osguthorpe
影响因子：
56.9
作者：
B. Wilkes;V. Hruby;A. M. Castrucci;W. C. Sherbrooke;M. Hadley
通讯作者：
B. Wilkes;V. Hruby;A. M. Castrucci;W. C. Sherbrooke;M. Hadley
黑色素浓缩激素的合成及其生物学作用。
DOI：
10.1016/s0006-291x(84)80077-7
发表时间：
1984
影响因子：
3.1
作者：
Wilkes,BC;Hruby,VJ;Sherbrooke,WC;Castrucci,AM;Hadley,ME
通讯作者：
Hadley,ME