Developmental Relationships of Four Exhausted CD8 + T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms

CD8 T cell exhaustion is a major barrier to current anti-cancer immunotherapies. Despite this, the developmental biology of exhausted CD8 T cells (Tex) remains poorly defined, restraining improvement of strategies aimed at "re-invigorating" Tex cells. Here, we defined a four-cell-stage dev...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Vol. 52; no. 5; p. 825
Main Authors: Beltra, Jean-Christophe, Manne, Sasikanth, Abdel-Hakeem, Mohamed S, Kurachi, Makoto, Giles, Josephine R, Chen, Zeyu, Casella, Valentina, Ngiow, Shin Foong, Khan, Omar, Huang, Yinghui Jane, Yan, Patrick, Nzingha, Kito, Xu, Wei, Amaravadi, Ravi K, Xu, Xiaowei, Karakousis, Giorgos C, Mitchell, Tara C, Schuchter, Lynn M, Huang, Alexander C, Wherry, E John
Format: Journal Article
Language:English
Published: United States 19.05.2020
Subjects:
Animals
B7-H1 Antigen - genetics
B7-H1 Antigen - immunology
CD8-Positive T-Lymphocytes - cytology
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - metabolism
Cells, Cultured
Epigenesis, Genetic - genetics
Epigenesis, Genetic - immunology
Hepatocyte Nuclear Factor 1-alpha - genetics
Hepatocyte Nuclear Factor 1-alpha - immunology
Homeodomain Proteins - genetics
Homeodomain Proteins - immunology
Humans
Immunotherapy - methods
Mice, Inbred C57BL
Neoplasms - genetics
Neoplasms - immunology
Neoplasms - therapy
T-Box Domain Proteins - genetics
T-Box Domain Proteins - immunology
T-Lymphocyte Subsets - immunology
T-Lymphocyte Subsets - metabolism
Transcription, Genetic - genetics
Transcription, Genetic - immunology
T cell exhaustion lineage
chronic infection
CD8
cancer immunotherapy
PD-1 blockade
exhaustion
Tox
T-bet
TCF1
epigenetics
ISSN:1097-4180, 1097-4180
Online Access:Get more information
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Summary:CD8 T cell exhaustion is a major barrier to current anti-cancer immunotherapies. Despite this, the developmental biology of exhausted CD8 T cells (Tex) remains poorly defined, restraining improvement of strategies aimed at "re-invigorating" Tex cells. Here, we defined a four-cell-stage developmental framework for Tex cells. Two TCF1 progenitor subsets were identified, one tissue restricted and quiescent and one more blood accessible, that gradually lost TCF1 as it divided and converted to a third intermediate Tex subset. This intermediate subset re-engaged some effector biology and increased upon PD-L1 blockade but ultimately converted into a fourth, terminally exhausted subset. By using transcriptional and epigenetic analyses, we identified the control mechanisms underlying subset transitions and defined a key interplay between TCF1, T-bet, and Tox in the process. These data reveal a four-stage developmental hierarchy for Tex cells and define the molecular, transcriptional, and epigenetic mechanisms that could provide opportunities to improve cancer immunotherapy.
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ISSN:1097-4180
1097-4180
DOI:10.1016/j.immuni.2020.04.014