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

• Published in: Immunity (Cambridge, Mass.) Vol. 52; no. 5; pp. 825 - 841.e8
• 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 Elsevier Inc 19.05.2020; Elsevier Limited
• Subjects: Animals; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; Biological effects; Biology; Cancer; Cancer immunotherapy; CD8; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell cycle; Cells, Cultured; chronic infection; Developmental biology; Epigenesis, Genetic - genetics; Epigenesis, Genetic - immunology; Epigenetics; Exhaustion; Hepatocyte nuclear factor 1; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte Nuclear Factor 1-alpha - immunology; Homeodomain Proteins - genetics; Homeodomain Proteins - immunology; Humans; Immunotherapy; Immunotherapy - methods; Infections; Lymphocytes; Lymphocytes T; Mice, Inbred C57BL; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - therapy; PD-1 blockade; PD-L1 protein; Population; T cell exhaustion lineage; T cell receptors; T-bet; T-Box Domain Proteins - genetics; T-Box Domain Proteins - immunology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; TCF1; Tox; Transcription; Transcription, Genetic - genetics; Transcription, Genetic - immunology; Tumors; Viral infections; T cell exhaustion lineage; chronic infection; CD8; cancer immunotherapy; exhaustion; PD-1 blockade; Tox; TCF1; T-bet; epigenetics
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2020.04.014

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. [Display omitted] •Ly108 and CD69 define four Tex subsets linked in a hierarchical developmental pathway•Two TCF1+ subsets, effector-like and terminally exhausted subsets, are identified•Key transcriptional, epigenetic, and biological changes define subset transitions•TCF1, T-bet, and Tox coordinate Tex subset development and dynamics Beltra et al. define a hierarchical developmental pathway for CD8+ T cell exhaustion, revealing four stages and multistep transcriptional and epigenetic dynamics underlying subset transitions and subset-associated biological changes.