CD28-driven ex vivo generation of stem-like memory CD8 <sup>+</sup> T cells bypassing CD3/TCR signaling

T cells, αCD28-aAPC stimulation initiates a distinct transcriptional and epigenetic program, marked by high TCF1 expression, metabolic fitness, and resistance to exhaustion-key hallmarks of the Tscm phenotype. Mechanistically, this approach circumvents canonical CD3/TCR signaling and notably avoids induction of IRF4, a key transcription factor that drives BLIMP1 upregulation, TCF1 downregulation, and glycolytic commitment during effector differentiation. Instead, sustained CD28 signaling alone reprograms T cells toward a Tscm-like state. Upon subsequent antigen encounter and CD3 engagement, these αCD28-aAPC-expanded T cells mount robust effector responses while retaining superior persistence and antitumor activity in preclinical models. Our findings reveal an underappreciated role of CD28 signaling in guiding Tscm-like fate through IRF4 suppression and establish a platform for generating durable and functionally potent T cell therapies.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2026-04-21
DOI
https://doi.org/10.1073/pnas.2524626123
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
0.00

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article

CD28-driven ex vivo generation of stem-like memory CD8 + T cells bypassing CD3/TCR signaling

Tak W. Mak, Kayoko Saso, Dong-Hoon Han, Naoto Hirano et al.
Proceedings of the National Academy of Sciences
CAR-T cell therapy research
article

CD28-driven ex vivo generation of stem-like memory CD8 + T cells bypassing CD3/TCR signaling

Tak W. Mak, Kayoko Saso, Dong-Hoon Han, Naoto Hirano, Samuel D. Saibil, Bo Wang, Dalam Ly, Yota Ohashi, Evey Y. F. Zheng, Brian D. Burt, Babak Noamani, Giselle M. Boukhaled, Saori Fukao, Yuki Kagoya, Fumie Ihara, Marcus O. Butler, Yukiko Matsunaga, Rowena Rodrigo, Xinyu Wei
article en

Abstract

T cells, αCD28-aAPC stimulation initiates a distinct transcriptional and epigenetic program, marked by high TCF1 expression, metabolic fitness, and resistance to exhaustion-key hallmarks of the Tscm phenotype. Mechanistically, this approach circumvents canonical CD3/TCR signaling and notably avoids induction of IRF4, a key transcription factor that drives BLIMP1 upregulation, TCF1 downregulation, and glycolytic commitment during effector differentiation. Instead, sustained CD28 signaling alone reprograms T cells toward a Tscm-like state. Upon subsequent antigen encounter and CD3 engagement, these αCD28-aAPC-expanded T cells mount robust effector responses while retaining superior persistence and antitumor activity in preclinical models. Our findings reveal an underappreciated role of CD28 signaling in guiding Tscm-like fate through IRF4 suppression and establish a platform for generating durable and functionally potent T cell therapies.

Proceedings of the National Academy of SciencesVol. 123(17)
University Health Network (CA), Chinese University of Hong Kong (HK), University of Toronto (CA), Hong Kong Science and Technology Parks Corporation (HK), Princess Margaret Cancer Centre (CA), Institute for Advanced Medical Research (US), University of Hong Kong (HK)
Princess Margaret Cancer Foundation, Ontario Institute for Cancer Research, Canada Research Chairs, Canadian Institutes of Health Research
Openalex Percentile: Top 17%
CAR-T cell therapy research
DOIOpen Access PDFOpenAlex
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