Krüppel-like factor 2 programs early exhausted T cell states and restrains antiviral immunity
(1) Geng S (2) Li Z (3) Li W (4) Liang H (5) Xu F (6) Zhang L (7) Zhang W (8) Tao S (9) Wang Y (10) Zhou Y (11) Luo S (12) Lei X (13) Li H (14) Huang WF (15) Che M (16) Liu WH (17) Huang J (18) Zhang T (19) Wang K (20) Xiao N (21) Mao K (22) Jiang Y (23) Huang H
Geng and Li et al. performed in vivo CRISPR screens in chronic LCMV infection and identified KLF2 as a central transcriptional regulator of CX3CR1+ effector-like exhausted (Texeff-like) CD8+ T cells. KLF2 directly engaged with Texeff-like loci, including Cx3cr1, and converted CX3CR1- cells into Texeff-like cells. KLF2 loss induced a TOX-dependent terminally exhausted state with enhanced activation, proliferation, and dendritic cell colocalization. KLF2 deficiency increased antigen-specific CD8+ T cell accumulation and improved viral control across stages of chronic infection. KLF2 and PD-1 co-deletion showed superior clearance, but with severe immunopathology.
Contributed by Shishir Pant
(1) Geng S (2) Li Z (3) Li W (4) Liang H (5) Xu F (6) Zhang L (7) Zhang W (8) Tao S (9) Wang Y (10) Zhou Y (11) Luo S (12) Lei X (13) Li H (14) Huang WF (15) Che M (16) Liu WH (17) Huang J (18) Zhang T (19) Wang K (20) Xiao N (21) Mao K (22) Jiang Y (23) Huang H
Geng and Li et al. performed in vivo CRISPR screens in chronic LCMV infection and identified KLF2 as a central transcriptional regulator of CX3CR1+ effector-like exhausted (Texeff-like) CD8+ T cells. KLF2 directly engaged with Texeff-like loci, including Cx3cr1, and converted CX3CR1- cells into Texeff-like cells. KLF2 loss induced a TOX-dependent terminally exhausted state with enhanced activation, proliferation, and dendritic cell colocalization. KLF2 deficiency increased antigen-specific CD8+ T cell accumulation and improved viral control across stages of chronic infection. KLF2 and PD-1 co-deletion showed superior clearance, but with severe immunopathology.
Contributed by Shishir Pant
ABSTRACT: A key challenge in improving T cell-mediated immunotherapies is defining the factors that regulate functional versus exhausted T cell fates. Through multi-round in vivo CRISPR screens in chronic lymphocytic choriomeningitis virus Clone 13 (LCMV Cl13) infection and transcription factor (TF) benchmarking, we identified Krppel-like factor 2 (KLF2) as a top TF driving CX3CR1(+) effector-like exhausted cell (Tex(eff-like)) differentiation. Overexpression of KLF2 converted CX3CR1_ cells into Tex(eff-like) cells by direct engagement of key loci. Conversely, loss of KLF2 increased inhibitory receptor expression and redirected cells toward terminal exhaustion. However, early after infection, KLF2 deficiency yielded increased CD8(+) T cell accumulation and improved viral control. This effect was, in part, mediated by TOX and improved T cell localization with dendritic cells. Additional deletion of PD-1 further enhanced viral control but induced severe immunopathology. Collectively, these findings identify KLF2 as a central regulator of the Tex(eff-like) program and underscore exhaustion features as checkpoints balancing antiviral immunity and immunopathology.
Author Info:
(1) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, X
iamen University, Xiamen, Fujian 361102, China. (2) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (3) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (4) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (5) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (6) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (7) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (8) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (9) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (10) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China. (11) National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian 361102, China. (12) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, Fujian 351002, China. (13) Department of Pharmacy, Xiamen Medical College, Xiamen, Fujian 361023, China. (14) Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China. (15) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China. (16) State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (17) National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (18) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, Fujian 351002, China. (19) School of Medicine, Xiamen University, South Xiang'an Road, Xiamen, Fujian 361102, China. (20) State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (21) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (22) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China. (23) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: honglinghuang@xmu.edu.cn.
