In vitro modeling of CD8 + T cell exhaustion enables CRISPR screening to reveal a role for BHLHE40
Year: 2023
Type: article
Abstract: Identifying novel 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, offering an opportunity to perform 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 pooled CRISPR screening to uncover 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 subsets of T ex . By developing and benchmarking an in vitro model of T ex , we demonstrate the utility of mechanistically annotated in vitro models of T ex , in combination with high-throughput approaches, as a discovery pipeline to uncover novel T ex biology.
Source: Science Immunology
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, Cancer Research Institute, Parker Institute for Cancer Immunotherapy, National Institutes of Health, National Health and Medical Research Council, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: Testing the role of BATF as a pioneer transcription factor in effector T cells, G1618383224, G1690409392, Training Program/Rheumatic Diseases, G2250081801, G2583384803, G2749247069, G2789168619, Molecular regulation of Tim3 signalling in T cells, Investigating molecular mechanism of immune response during cancer progression, G41353926, G4424250656, G660146901, Temporal control of differentiation and epigenetics of Exhausted CD8 T cells by Tox, G9000024465, G9000077235, G9000091755, G9000140237, G9000178764, G9000221685, G9000299776, G9000323715, G9000341336
OpenAlex ID: W4385975202