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  • Open Access

Fas expression in memory CD8+ T cell subsets augments cellular differentiation and effector function

  • 1,
  • 1,
  • 2,
  • 2,
  • 3,
  • 4,
  • 4,
  • 4,
  • 1 and
  • 1
Journal for ImmunoTherapy of Cancer20153 (Suppl 2) :P329

https://doi.org/10.1186/2051-1426-3-S2-P329

  • Published:

Keywords

  • Lipid Raft
  • Cellular Differentiation
  • Chimeric Antigen Receptor
  • Cell Immunotherapy
  • Antibody Blockade

Memory CD8+ T cells (TMem) have the capacity to provide lifelong host 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 been shown to mediate non-death signaling in other cell types, we 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 resulted in augmented cellular differentiation and a loss in IL-2 secretion capacity. Conversely, antibody blockade (anti-FasL) of Fas signaling in TCM retarded cellular differentiation both phenotypically and functionally. To genetically disentangle the pro-apoptotic and differentiation signals from Fas, we made use of a mutant Fas lacking a transmembrane cysteine residue (FasC194V) that is unable to undergo S-palmitoylation and aggregate efficiently in lipid rafts. Using transgenic mice expressing this C194V Fas construct on a Fas-deficient lpr background, we found that FasC194V TMem can still undergo cellular differentiation in the absence of death signaling. In vivo, TMem expanded with anti-FasL showed greater expansion, on-target immunity and withheld differentiation. Additionally, in a relevant syngeneic model of current human T cell immunotherapy, TMem cells expanded with anti-FasL and genetically engineered with an anti-CD19 chimeric antigen receptor (CAR) exhibited enhanced CAR expression, reduced differentiation, and augmented anti-lymphoma activity compared to controls. These studies demonstrate that Fas signaling promotes not only cell death but also TMem effector differentiation, a finding that has implications for the design and execution of T cell-based immunotherapies in patients with cancer or infectious disease.

Authors’ Affiliations

(1)
Center for Cancer Research, NCI/NIH, Bethesda, MD, USA
(2)
Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, MD, USA
(3)
Experimental Transplantation and Immunology Branch, NCI/NIH, Bethesda, MD, USA
(4)
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, USA

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