Shared and distinct biological circuits in effector, memory and exhausted CD8 + T cells revealed by temporal single-cell transcriptomics and epigenetics

Naïve CD8 T cells can differentiate into effector (T ), memory (T ) or exhausted (T ) T cells. These developmental pathways are associated with distinct transcriptional and epigenetic changes that endow cells with different functional capacities and therefore therapeutic potential. The molecular cir...

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Veröffentlicht in:Nature immunology Jg. 23; H. 11; S. 1600 - 1613
Hauptverfasser: Giles, Josephine R, Ngiow, Shin Foong, Manne, Sasikanth, Baxter, Amy E, Khan, Omar, Wang, Ping, Staupe, Ryan, Abdel-Hakeem, Mohamed S, Huang, Hua, Mathew, Divij, Painter, Mark M, Wu, Jennifer E, Huang, Yinghui Jane, Goel, Rishi R, Yan, Patrick K, Karakousis, Giorgos C, Xu, Xiaowei, Mitchell, Tara C, Huang, Alexander C, Wherry, E John
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Nature Publishing Group 01.11.2022
Schlagworte:
Apoptosis
CD8 antigen
CD8-Positive T-Lymphocytes - metabolism
Cell differentiation
Cellular stress response
Chromatin
Chromatin - genetics
Chromatin - metabolism
Chronic infection
Circuits
Comparative analysis
Cytotoxicity
Effector cells
Epigenesis, Genetic
Epigenetics
Hepatocyte nuclear factor 1
Heterogeneity
Humans
Immunological memory
Infections
Lymphocytes
Lymphocytes T
Lymphocytic Choriomeningitis - metabolism
Lymphocytic choriomeningitis virus
Memory cells
Natural killer cells
PD-1 protein
Transcriptome
Transcriptomics
Transposase
ISSN:1529-2908, 1529-2916, 1529-2916
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Zusammenfassung:Naïve CD8 T cells can differentiate into effector (T ), memory (T ) or exhausted (T ) T cells. These developmental pathways are associated with distinct transcriptional and epigenetic changes that endow cells with different functional capacities and therefore therapeutic potential. The molecular circuitry underlying these developmental trajectories and the extent of heterogeneity within T , T and T populations remain poorly understood. Here, we used the lymphocytic choriomeningitis virus model of acute-resolving and chronic infection to address these gaps by applying longitudinal single-cell RNA-sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analyses. These analyses uncovered new subsets, including a subpopulation of T cells expressing natural killer cell-associated genes that is dependent on the transcription factor Zeb2, as well as multiple distinct TCF-1 stem/progenitor-like subsets in acute and chronic infection. These data also revealed insights into the reshaping of T subsets following programmed death 1 (PD-1) pathway blockade and identified a key role for the cell stress regulator, Btg1, in establishing the T population. Finally, these results highlighted how the same biological circuits such as cytotoxicity or stem/progenitor pathways can be used by CD8 T cell subsets with highly divergent underlying chromatin landscapes generated during different infections.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1529-2908
1529-2916
1529-2916
DOI:10.1038/s41590-022-01338-4