Journal
NATURE BIOTECHNOLOGY
Volume 37, Issue 3, Pages 259-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41587-019-0033-2
Keywords
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Categories
Funding
- NIH [5T32AI007290-29, 5T32AI007290-30, 5T32AI007290-32, 5T32AI007290-33, 2T32AI007290-31, R01CA184968, 1R01GM10983601, 1R01NS08953301, 1R01CA19665701, R01HL120724, 1R21CA183660, R33CA0183692, 1R33CA183654-01]
- NIH Northrop-Grumman Corporation [7500108142]
- FDA grant [HHSF223201210194C]
- DOD [OC110674, W81XWH-14-1-0180]
- NWCRA Entertainment Industry Foundation
- Bill and Melinda Gates Foundation [OPP1113682]
- Damon Runyon Cancer Research Foundation Fellowship [DRG-2017-09]
- Stanford Cancer Institute
- [5UH2AR067676]
- [1DP2OD022550-01]
- [1R01AG056287-01]
- [1R01AG057915-01]
- [1-R00-GM104148-01]
- [1U24CA224309-01]
- [5U19AI116484-02]
- [U19 AI104209]
- [S10OD018220]
- [U19AI057229]
- [1U19AI100627]
- [U54-UCA149145A]
- [N01-HV-00242 HHSN26820100034C]
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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 (T-SCM)-like phenotype. This method for tracing cell fate across division states and time can be broadly applied for directing cellular differentiation.
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