Ectopic Tcf1 expression instills a stem-like program in exhausted CD8^(+) T cells to enhance viral and tumor immunity

作     者：Qiang Shan Sheng’en Hu Xia Chen Derek B.Danahy Vladimir P.Badovinac Chongzhi Zang Hai-Hui Xue 

作者机构：Center for Discovery and InnovationHackensack Meridian HealthNutleyNJ07110USA Department of Microbiology and ImmunologyCarver College of MedicineUniversity of IowaIowa CityIA52242USA Center for Public Health GenomicsUniversity of Virginia School of MedicineCharlottesvilleVA22908USA Department of PathologyCarver College of MedicineUniversity of IowaIowa CityIA52242USA Interdisciplinary Immunology Graduate ProgramCarver College of MedicineUniversity of IowaIowa CityIA52242USA Iowa City Veterans Affairs Health Care SystemIowa CityIA52246USA 

出 版 物：《Cellular & Molecular Immunology》 (中国免疫学杂志（英文版）)

年 卷 期：2021年第18卷第5期

页      面：1262-1277页

核心收录：

学科分类：1001[医学-基础医学(可授医学、理学学位)] 100102[医学-免疫学] 10[医学] 

基　　金：supported by grants from the NIH(AI112579,AI121080 and AI139874 to H.-H.X.,GM133712 to C.Z.,and GM113961,AI147064 and AI114543 to V.P.B.) the Veteran Affairs BLR&D Merit Review Program(BX002903)to H.-H.X 

主　　题：T cell exhaustion Tcf1 Stem cell features 

摘      要：Exhausted CD8^(+)T(Tex)cells are dysfunctional due to persistent antigen exposure in chronic viral infection and tumor contexts.A stem cell-like Tex(Tex-stem)subset can self-renew and differentiate into terminally exhausted(Tex-term)***,we show that ectopic Tcf1 expression potently promoted the generation of Tex-stem cells in both a chronic viral infection and preclinical tumor ***1 overexpression diminished coinhibitory receptor expression and enhanced polycytokine-producing capacity while retaining a heightened responses to checkpoint blockade,leading to enhanced viral and tumor ***,ectopically expressed Tcf1 exploited existing and novel chromatin accessible sites as transcriptional enhancers or repressors and modulated the transcriptome by enforcing pre-existing expression patterns in Tex-stem cells,such as enhanced suppression of Blimp1 and Bim and acquisition of new downstream genes,including Mx1,Tox2,and *** findings reveal a pronounced impact of ectopic Tcf1 expression on Tex functional restoration and highlight the therapeutic potential of harnessing Tcf1-enforced transcriptional programs.