T-bet deficiency and Hic1 induction override TGF-β-dependency in the formation of CD103+ intestine-resident memory CD8+ T cells
Liwen Wang,
Shruti Mishra,
Kenneth Ka-Ho Fan,
Sara Quon,
Guo Li,
Bingfei Yu,
Wei Liao,
Yong Liu,
Xin Zhang,
Yuanzheng Qiu,
Yue Li,
Ananda W. Goldrath,
Chaoyu Ma,
Nu Zhang
Affiliations
Liwen Wang
Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
Shruti Mishra
Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Kenneth Ka-Ho Fan
Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Sara Quon
Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
Guo Li
Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China; Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Clinical Research Center for Laryngopharyngeal and Voice Disorders in Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
Bingfei Yu
Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
Wei Liao
Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
Yong Liu
Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China; Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Clinical Research Center for Laryngopharyngeal and Voice Disorders in Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
Xin Zhang
Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China; Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Clinical Research Center for Laryngopharyngeal and Voice Disorders in Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
Yuanzheng Qiu
Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China; Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Clinical Research Center for Laryngopharyngeal and Voice Disorders in Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
Yue Li
Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Ananda W. Goldrath
Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
Chaoyu Ma
Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Corresponding author
Nu Zhang
Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; South Texas Veterans Health Care System, San Antonio, TX 78229, USA; Corresponding author
Summary: Transforming growth factor β (TGF-β) represents a well-established signal required for tissue-resident memory T cell (TRM) formation at intestinal surfaces, regulating the expression of a large collection of genes coordinately promoting intestinal TRM differentiation. The functional contribution from each TGF-β-controlled transcription factor is not entirely known. Here, we find that TGF-β-induced T-bet downregulation and Hic1 induction represent two critical events during intestinal TRM differentiation. Importantly, T-bet deficiency significantly rescues intestinal TRM formation in the absence of the TGF-β receptor. Hic1 induction further strengthens TRM maturation in the absence of TGF-β and T-bet. Our results reveal that provision of certain TGF-β-induced molecular events can partially replace TGF-β signaling to promote the establishment of intestinal TRMs, which allows the functional dissection of TGF-β-induced transcriptional targets and molecular mechanisms for TRM differentiation.
