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Nat Biotechnol. 2019 Mar;37(3):259-266. doi: 10.1038/s41587-019-0033-2. Epub 2019 Feb 11.

Proliferation tracing with single-cell mass cytometry optimizes generation of stem cell memory-like T cells.

Author information

1
PhD Program in Immunology, Stanford University, Stanford, CA, USA.
2
Baxter Laboratory in Stem Cell Biology, Stanford University, Stanford, CA, USA.
3
Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA.
4
Department of Pathology, Stanford University, Stanford, CA, USA.
5
Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
6
Cancer Institute, Department of Medicine, Stanford University, Stanford, CA, USA.
7
Department of Statistics, Stanford University, Stanford, CA, USA.
8
Department of Health Research and Policy, Stanford University, Stanford, CA, USA.
9
Department of Pathology, Stanford University, Stanford, CA, USA. bendall@stanford.edu.
10
Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. bendall@stanford.edu.

Abstract

Selective differentiation of naive T cells into multipotent T cells is of great interest clinically for the generation of cell-based cancer immunotherapies. Cellular differentiation depends crucially on division state and time. Here we adapt a dye dilution assay for tracking cell proliferative history through mass cytometry and uncouple division, time and regulatory protein expression in single naive human T cells during their activation and expansion in a complex ex vivo milieu. Using 23 markers, we defined groups of proteins controlled predominantly by division state or time and found that undivided cells account for the majority of phenotypic diversity. We next built a map of cell state changes during naive T-cell expansion. By examining cell signaling on this map, we rationally selected ibrutinib, a BTK and ITK inhibitor, and administered it before T cell activation to direct differentiation toward a T stem cell memory (TSCM)-like phenotype. This method for tracing cell fate across division states and time can be broadly applied for directing cellular differentiation.

PMID:
30742126
DOI:
10.1038/s41587-019-0033-2

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