Naive-derived CD8+ T cells possess a superior capacity to engraft, expand, and mediate tumor regression following adoptive transfer compared to memory-derived T cells. However, whether the antigen-experienced subsets may directly influence naive cell differentiation is unknown. We show that human and mouse memory lymphocytes caused naive T cells to undergo augmented differentiation following priming both in vitro and in vivo. This process, which we term precocious differentiation, resulted in the accelerated functional, transcriptional, and metabolic differentiation of TN-derived progeny. Precocious differentiation was mediated by non-apoptotic Fas signaling delivered by memory cells to naive cells resulting in Akt-driven cellular differentiation. Consequently, blockade of Fas-signaling prevented TMem-induced precocious differentiation and preserved the antitumor efficacy of TN-derived cells while induction of Fas-signaling in the absence of TMem enhanced differentiation and impaired antitumor immunity. Collectively, our results reveal that unleashing the therapeutic potential of TN-derived cells requires disruption of cellular communication with TMem, a finding with significant implications for the design and execution of T cell therapy clinical trials.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Basic Sciences
Zip Code
Klebanoff, Christopher A; Scott, Christopher D; Leonardi, Anthony J et al. (2016) Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. J Clin Invest 126:318-34
Crompton, Joseph G; Narayanan, Manikandan; Cuddapah, Suresh et al. (2016) Lineage relationship of CD8(+) T cell subsets is revealed by progressive changes in the epigenetic landscape. Cell Mol Immunol 13:502-13
Klebanoff, Christopher A; Rosenberg, Steven A; Restifo, Nicholas P (2016) Prospects for gene-engineered T cell immunotherapy for solid cancers. Nat Med 22:26-36