In vitro modeling of CD8+ T cell exhaustion enables CRISPR screening to reveal a role for BHLHE40

被引：26

作者：

Wu, Jennifer E. E. ^{[1
,2
,3
]}

Manne, Sasikanth ^{[1
,2
]}

Ngiow, Shin Foong ^{[1
,2
,3
]}

Baxter, Amy E. ^{[1
,2
]}

Huang, Hua ^{[1
,2
,5
]}

Freilich, Elizabeth ^{[4
,5
]}

Clark, Megan L. ^{[2
,6
]}

Lee, Joanna H. H. ^{[1
,2
]}

Chen, Zeyu ^{[1
,2
,7
]}

Khan, Omar ^{[1
,2
,8
]}

Staupe, Ryan P. ^{[1
,2
,9
]}

Huang, Yinghui J. J. ^{[1
,2
]}

Shi, Junwei ^{[2
,4
,5
]}

Giles, Josephine R. ^{[1
,2
,3
]}

Wherry, E. John ^{[1
,2
,3
]}

机构：

[1] Univ Penn, Perelman Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA

[2] Univ Penn, Inst Immunol & Immune Hlth, Perelman Sch Med, Philadelphia, PA 19104 USA

[3] Univ Penn, Parker Inst Canc Immunotherapy, Philadelphia, PA 19104 USA

[4] Univ Penn, Perelman Sch Med, Dept Canc Biol, Philadelphia, PA USA

[5] Univ Penn, Epigenet Inst, Perelman Sch Med, Philadelphia, PA USA

[6] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA USA

[7] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA

[8] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA USA

[9] Merck & Co Inc, Infect Dis & Vaccines, MRL, West Point, PA USA

来源：

SCIENCE IMMUNOLOGY | 2023年 / 8卷 / 86期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

TERMINAL DIFFERENTIATION; TRANSCRIPTION FACTORS; EPIGENETIC LANDSCAPE; EFFECTOR; PD-1; INFECTION; SUBSETS; GENES; ZEB2; ACCUMULATION;

D O I：

10.1126/sciimmunol.ade3369

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Identifying molecular mechanisms of exhausted CD8 T cells (T-ex) is a key goal of improving immunotherapy of cancer and other diseases. However, high-throughput interrogation of in vivo T-ex can be costly and inefficient. In vitro models of T-ex are easily customizable and quickly generate high cellular yield, enabling CRISPR screening and other high-throughput assays. We established an in vitro model of chronic stimulation and benchmarked key phenotypic, functional, transcriptional, and epigenetic features against bona fide in vivo T-ex. We leveraged this model of in vitro chronic stimulation in combination with CRISPR screening to identify transcriptional regulators of T cell exhaustion. This approach identified several transcription factors, including BHLHE40. In vitro and in vivo validation defined a role for BHLHE40 in regulating a key differentiation checkpoint between progenitor and intermediate T-ex subsets. By developing and benchmarking an in vitro model of T-ex, then applying high-throughput CRISPR screening, we demonstrate the utility of mechanistically annotated in vitro models of T-ex.

引用

页数：16

共 81 条

[1] Impaired NFAT nuclear translocation results in split exhaustion of virus-specific CD8+ T cell functions during chronic viral infection [J].