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Fas expression in memory CD8+ T cell subsets augments cellular differentiation and effector function
© Yamamoto et al. 2015
Published: 4 November 2015
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.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.