Memory CD8+ T cells (TMem) have the capacity to provide lifelong protection against intracellular pathogens and cancer. Despite phenotypic and functional heterogeneity among TMem, the expression of Fas, a tumor necrosis family receptor (TNFR) superfamily member conventionally known as a death receptor, is held in common among all TMem subsets across multiple species. As Fas has also been shown to mediate other effects besides death signaling, we therefore set out to elucidate the role of Fas signaling in defined TMem subsets, including T stem cell memory (TSCM), T central memory (TCM), and T effector memory (TEM). We found that augmenting Fas signaling in stimulated TSCM using an oligomerized form of its ligand FasL (lz-FasL) resulted in augmented cellular differentiation and a corresponding loss in IL-2 secretion capacity. Conversely, deprivation of Fas signaling in TCM using a blocking, non-agonistic antibody to FasL (aFasL) retarded cellular differentiation. Gene expression analysis demonstrated that TMem expanded with aFasL expressed greater levels of memory-associated transcription factors relative to IgG-treated controls. Moreover, preventing Fas-signaling significantly altered the metabolic state of activated TMem, most notably by limiting the acquisition of glycolytic metabolism. When used in vivo, TMem expanded with aFasL showed greater on-target immunity compared to IgG controls. These studies demonstrate that Fas signaling promotes not only cell death but also TMem differentiation towards a more effector-like state, a finding which has implications for the design and execution of clinical trials T cell-based immunotherapies in patients with cancer and infectious disease.
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