Abstract
T-cell dysfunction arising upon repeated antigen exposure prevents effective immunity and immunotherapy. Using various clinically and physiologically relevant systems, we show that a prominent feature of PD-1-expressing exhausted T cells is the development of cellular senescence features both in vivo and ex vivo. This is associated with p16INK4a expression and an impaired cell cycle G1 to S-phase transition in repeatedly stimulated T cells. We show that these T cells accumulate DNA damage and activate the p38MAPK signaling pathway, which preferentially leads to p16INK4a upregulation. However, in highly dysfunctional T cells, p38MAPK inhibition does not restore functionality despite attenuating senescence features. In contrast, p16INK4a targeting can improve T-cell functionality in exhausted CAR T cells. Collectively, this work provides insights into the development of T-cell dysfunction and identifies T-cell senescence as a potential target in immunotherapy.
Highlights
The capacity of conventional T cells to control or eradicate pathogens and transformed cells is compromised following repeated stimulations, owing to the development of T-cell dysfunction
This is associated with p16INK4a expression and an impaired cell cycle G1 to S-phase transition in repeatedly stimulated T cells. We show that these T cells accumulate DNA damage and activate the p38MAPK signaling pathway, which preferentially leads to p16INK4a upregulation
T cells were characterized after a single stimulation and compared with cells harvested after two consecutive weeks of halted proliferation, occurring between 35-49 days
Summary
The capacity of conventional T cells to control or eradicate pathogens and transformed cells is compromised following repeated stimulations, owing to the development of T-cell dysfunction. As such, repeated antigenic encounters in the setting of chronic infections or cancer, as well as the extensive culture required for the generation of sufficient cell numbers for treatment in certain adoptive cell therapy (ACT) settings, are conducive to the induction of T-cell terminal differentiation, exhaustion, senescence or apoptosis [2]. Whether these cellular states are distinct, partially overlapping, co-regulated or part of a continuum remains incompletely understood. Cellular senescence can be triggered by various forms of cellular stress and is characterized by prolonged cell cycle arrest as well the acquisition of several features including morphological changes, chromatin remodeling, metabolic reprogramming, and secretion of multiple factors collectively called the senescence-associated secretory phenotype (SASP) [6]
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