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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Vydáno v:	Immunity (Cambridge, Mass.) Ročník 52; číslo 5; s. 825
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 19.05.2020
Témata:	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
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4180 1097-4180
DOI:	10.1016/j.immuni.2020.04.014