Opposing regulatory functions of the TIM3 (HAVCR2) signalosome in primary effector T cells as revealed by quantitative interactomics  

作　　者：Yunhao Zhai Javier Celis-Gutierrez Guillaume Voisinne Daiki Mori Laura Girard Odile Burlet-Schiltz Anne Gonzalez de Peredo Romain Roncagalli Bernard Malissen 

机构地区：[1]Centre d’Immunologie de Marseille-Luminy,Aix Marseille Université,INSERM,CNRS,13288,Marseille,France [2]Centre d’Immunophénomique,Aix Marseille Université,INSERM,CNRS,Marseille,France [3]Institut de Pharmacologie et de Biologie Structurale,Département Biologie Structurale Biophysique,Protéomique Génopole Toulouse Midi Pyrénées CNRS UMR 5089,Toulouse,France

出　　处：《Cellular & Molecular Immunology》2021年第6期1581-1583,共3页中国免疫学杂志（英文版）

基　　金：supported by CNRS,INSERM,the European Research Council(ERC)under the European Union's Horizon 2020 research and innovation program(Grant agreement n°787300(BASILIC)to B.M.),ANR(SUPERBASILIC Project to B.M.),Plan Cancer 2015-Projet Cl 5091 AS(to B.M.),the MSDAvenir Fund(to B.M.),the Investissement d'Avenir program PHENOMIN(ANR-10-INBS-07,to B.M.),the ProFi(ANR-10-INBS-08 to O.B.-S.),and fellowships from DC Biol Labex(ANR-11-LABEX-0043,grant ANR-10-IDEX-0001-02 PSL,J.C.-G.),the China Scholarship Council(YZ.),the ANR(YZ.),and MSDAvenir(D.M.).

摘　　要：Deciphering how T-cell antigen receptor signals are modulated by coinhibitors is a fundamental goal in immunology and of considerable clinical interest because blocking coinhibitory signals via therapeutic antibodies have become a standard cancer immunotherapeutic strategy.Most of the attention devoted to T-cell immunoglobulin and mucin domain-3(TIM3;also known as HAVCR2 or CD366)molecules stems from their expression on exhausted T cells in settings of chronic viral infection and tumors.Moreover,T cells expressing high levels of both PD-1 and TIM3 coinhibitors appear more dysfunctional than those expressing PD-1 alone.Combination therapies intending to block both PD-1 and TIM3 are thus actively being explored in the cancer treatment setting.Upon interaction with Galectin-9(GAL-9)and carcinoembryonic antigen-related cell adhesion molecule 1(CEACAM-1),the tyrosines found in the TIM3 cytoplasmic tail are phosphorylated.1 Because these conserved tyrosines do not form a recognizable inhibitory signaling motif,the mechanism by which TIM3 transmits inhibitory signals has not been elucidated.Paradoxically,TIM3 also has costimulatory activity in T cells.2,3 Published biochemical studies attempting to unveil the mode of action of TIM3 have relied on approaches addressing one candidate effector at a time with limited quantitative insight,and most used transformed cells.Using mice expressing an affinity Twin-Strep-tag(OST)at the TIM3-protein C-terminus(TIM3OST mice)(Figs.1a and S1a)and affinity purification coupled with mass spectrometry(AP-MS),we herein defined the composition and dynamics of the signaling protein complex(signalosome)used by TIM3 in primary effector T cells.These results provide a more complete model of TIM3 signaling and explain its paradoxical coinhibitory and costimulatory functions.

关 键 词：TIM3 EXPRESSING devoted 

分 类 号：R392[医药卫生—免疫学]