Tumor-induced double positive T cells display distinct lineage commitment mechanisms and functions

Transcription factors ThPOK and Runx3 regulate the differentiation of "helper" CD4+ and "cytotoxic" CD8+ T cell lineages respectively, inducing single positive (SP) T cells that enter the periphery with the expression of either the CD4 or CD8 co-receptor. Despite the expectation...

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Published in:The Journal of experimental medicine Vol. 219; no. 6
Main Authors: Schad, Sara E, Chow, Andrew, Mangarin, Levi, Pan, Heng, Zhang, Jiajia, Ceglia, Nicholas, Caushi, Justina X, Malandro, Nicole, Zappasodi, Roberta, Gigoux, Mathieu, Hirschhorn, Daniel, Budhu, Sadna, Amisaki, Masataka, Arniella, Monica, Redmond, David, Chaft, Jamie, Forde, Patrick M, Gainor, Justin F, Hellmann, Matthew D, Balachandran, Vinod, Shah, Sohrab, Smith, Kellie N, Pardoll, Drew, Elemento, Olivier, Wolchok, Jedd D, Merghoub, Taha
Format: Journal Article
Language:English
Published: United States 06.06.2022
Subjects:
Animals
CD4 Antigens - metabolism
CD4-Positive T-Lymphocytes
CD8 Antigens - metabolism
CD8-Positive T-Lymphocytes
Cell Differentiation
Cell Lineage - genetics
Melanoma - metabolism
Mice
T-Lymphocyte Subsets
ISSN:1540-9538, 1540-9538
Online Access:Get more information
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Summary:Transcription factors ThPOK and Runx3 regulate the differentiation of "helper" CD4+ and "cytotoxic" CD8+ T cell lineages respectively, inducing single positive (SP) T cells that enter the periphery with the expression of either the CD4 or CD8 co-receptor. Despite the expectation that these cell fates are mutually exclusive and that mature CD4+CD8+ double positive (DP) T cells are present in healthy individuals and augmented in the context of disease, yet their molecular features and pathophysiologic role are disputed. Here, we show DP T cells in murine and human tumors as a heterogenous population originating from SP T cells which re-express the opposite co-receptor and acquire features of the opposite cell type's phenotype and function following TCR stimulation. We identified distinct clonally expanded DP T cells in human melanoma and lung cancer by scRNA sequencing and demonstrated their tumor reactivity in cytotoxicity assays. Our findings indicate that antigen stimulation induces SP T cells to differentiate into DP T cell subsets gaining in polyfunctional characteristics.
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ISSN:1540-9538
1540-9538
DOI:10.1084/jem.20212169