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

Sara E. Schad, Andrew Chow, Levi Mangarin, Heng Pan, Jiajia Zhang, Nicholas Ceglia, Justina X. Caushi, Nicole Malandro, Roberta Zappasodi, Mathieu Gigoux, Daniel Hirschhorn, Sadna Budhu, Masataka Amisaki, Monica Arniella, David Redmond, Jamie Chaft, Patrick M. Forde, Justin F. Gainor, Matthew D. Hellmann, Vinod BalachandranSohrab Shah, Kellie N. Smith, Drew Pardoll, Olivier Elemento, Jedd D. Wolchok, Taha Merghoub

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbere20212169
JournalJournal of Experimental Medicine
Issue number6
StatePublished - Jun 6 2022

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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