The SKI proto-oncogene restrains the resident CD103^(+)CD8^(+) T cell response in viral clearance  

作　　者：Bing Wu Ge Zhang Zengli Guo Gang Wang Xiaojiang Xu Jian-liang Li Jason K.Whitmire Junnian Zheng Yisong Y.Wan 

机构地区：[1]Lineberger Comprehensive Cancer Center,School of Medicine,University of North Carolina at Chapel Hill,Chapel Hill,NC 27599,USA [2]Department of Microbiology and Immunology,School of Medicine,University of North Carolina at Chapel Hill,Chapel Hill,NC 27599,USA [3]Department of Immunology,College of Basic Medical Science,Dalian Medical University,Dalian,Liaoning 116044,China [4]Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,Cancer Institute,Xuzhou Medical University,Xuzhou,Jiangsu,221002,China [5]Integrative Bioinformatics,National Institute of Environmental Health Sciences,Research Triangle Park,Chapel Hill,NC 27709,USA [6]Department of Genetics,School of Medicine,University of North Carolina at Chapel Hill,Chapel Hill,NC 27599,USA

出　　处：《Cellular & Molecular Immunology》2021年第10期2410-2421,共12页中国免疫学杂志（英文版）

基　　金：This work was supported by NIH funding(R01Al143894,R01Al138337)for J.K.W.;the NIH(Al123193);the National Multiple Sclerosis Society(RG-1802-30483);the Yang Family Biomedical Scholars Award for Y.Y.W.

摘　　要：Acute viral infection causes illness and death.In addition,an infection often results in increased susceptibility to a secondary infection,but the mechanisms behind this susceptibility are poorly understood.Since its initial identification as a marker for resident memory CD8^(+)T cells in barrier tissues,the function and regulation of CD103 integrin(encoded by ITGAE gene)have been extensively investigated.Nonetheless,the function and regulation of the resident CD103^(+)CD8^(+)T cell response to acute viral infection remain unclear.Although TGFβsignaling is essential for CD103 expression,the precise molecular mechanism behind this regulation is elusive.Here,we reveal a TGFβ–SKI–Smad4 pathway that critically and specifically directs resident CD103^(+)CD8^(+)T cell generation for protective immunity against primary and secondary viral infection.We found that resident CD103^(+)CD8^(+)T cells are abundant in both lymphoid and nonlymphoid tissues from uninfected mice.CD103 acts as a costimulation signal to produce an optimal antigenic CD8^(+)T cell response to acute viral infection.There is a reduction in resident CD103^(+)CD8^(+)T cells following primary infection that results in increased susceptibility of the host to secondary infection.Intriguingly,CD103 expression inversely and specifically correlates with SKI proto-oncogene(SKI)expression but not R-Smad2/3 activation.Ectopic expression of SKI restricts CD103 expression in CD8^(+)T cells in vitro and in vivo to hamper viral clearance.Mechanistically,SKI is recruited to the Itgae loci to directly suppress CD103 transcription by regulating histone acetylation in a Smad4-dependent manner.Our study therefore reveals that resident CD103^(+)CD8^(+)T cells dictate protective immunity during primary and secondary infection.Interfering with SKI function may amplify the resident CD103^(+)CD8^(+)T cell response to promote protective immunity.

关 键 词：CD103 TGFΒ SKI SMAD4 LCMV infection Histone acetylation 

分 类 号：R392[医药卫生—免疫学]