Faculty, Staff and Student Publications

Language

English

Publication Date

1-1-2024

Journal

Nature Immunology

DOI

10.1038/s41590-023-01685-w

PMID

38012417

PMCID

PMC10841689

PubMedCentral® Posted Date

1-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

During cancers and infections, self-renewing stem-like CD8+ T cells mediate the response of immunotherapies and replenish terminally exhausted T cells and effector-like T cells. However, the programs governing the lineage choice in chimeric antigen receptor (CAR) T cells are unclear. Here, by simultaneously profiling single-cell chromatin accessibility and transcriptome in the same CAR T cells, we identified heterogeneous chromatin states within CD8+ T cell subsets that foreshadowed transcriptional changes and were primed for regulation by distinct transcription factors. Transcription factors that controlled each CD8+ T cell subset were regulated by high numbers of enhancers and positioned as hubs of gene networks. FOXP1, a hub in the stem-like network, promoted expansion and stemness of CAR T cells, and limited excessive effector differentiation. In the effector network, KLF2 enhanced effector CD8+ T cell differentiation and prevented terminal exhaustion. Thus, we identified gene networks and hub transcription factors that controlled the differentiation of stem-like CD8+ CAR T cells into effector or exhausted CD8+ CAR T cells.

Keywords

CD8-Positive T-Lymphocytes, Transcription Factors, T-Lymphocyte Subsets, Cell Differentiation, Chromatin

Published Open-Access

yes

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