High mTOR activity is a hallmark of reactive natural killer cells and amplifies early signaling through activating receptors

Author:

Marçais Antoine12345ORCID,Marotel Marie12345,Degouve Sophie12345,Koenig Alice12345,Fauteux-Daniel Sébastien12345,Drouillard Annabelle12345,Schlums Heinrich6,Viel Sébastien12345,Besson Laurie12345,Allatif Omran12345,Bléry Mathieu7,Vivier Eric89,Bryceson Yenan610,Thaunat Olivier12345,Walzer Thierry12345ORCID

Affiliation:

1. CIRI, Centre International de Recherche en Infectiologie - International Center for Infectiology Research, Lyon, France

2. Inserm, U1111, Lyon, France

3. Ecole Normale Supérieure de Lyon, Lyon, France

4. Université Lyon 1, Lyon, France

5. CNRS, UMR5308, Lyon, France

6. Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden

7. Innate-Pharma, Marseille, France

8. Aix-Marseille Université, CNRS, INSERM, CIML, Marseille, France

9. APHM, Hôpital de la Timone, Service d’Immunologie, Marseille, France

10. Broegelmann Research Laboratory, The Gades Institute, University of Bergen, Bergen, Norway

Abstract

NK cell education is the process through which chronic engagement of inhibitory NK cell receptors by self MHC-I molecules preserves cellular responsiveness. The molecular mechanisms responsible for NK cell education remain unclear. Here, we show that mouse NK cell education is associated with a higher basal activity of the mTOR/Akt pathway, commensurate to the number of educating receptors. This higher activity was dependent on the SHP-1 phosphatase and essential for the improved responsiveness of reactive NK cells. Upon stimulation, the mTOR/Akt pathway amplified signaling through activating NK cell receptors by enhancing calcium flux and LFA-1 integrin activation. Pharmacological inhibition of mTOR resulted in a proportional decrease in NK cell reactivity. Reciprocally, acute cytokine stimulation restored reactivity of hyporesponsive NK cells through mTOR activation. These results demonstrate that mTOR acts as a molecular rheostat of NK cell reactivity controlled by educating receptors and uncover how cytokine stimulation overcomes NK cell education.

Funder

Agence Nationale de la Recherche

H2020 European Research Council

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3