Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction

Abstract

Mutations affecting the apoptosis-inducing function of the Fas/CD95 TNF-family receptor result in autoimmune and lymphoproliferative disease. However, Fas can also costimulate T-cell activation and promote tumour cell growth and metastasis. Palmitoylation at a membrane proximal cysteine residue enables Fas to localize to lipid raft microdomains and induce apoptosis in cell lines. Here, we show that a palmitoylation-defective Fas C194V mutant is defective in inducing apoptosis in primary mouse T cells, B cells and dendritic cells, while retaining the ability to enhance naive T-cell differentiation. Despite inability to efficiently induce cell death, the Fas C194V receptor prevents the lymphoaccumulation and autoimmunity that develops in Fas-deficient mice. These findings indicate that induction of apoptosis through Fas is dependent on receptor palmitoylation in primary immune cells, and Fas may prevent autoimmunity by mechanisms other than inducing apoptosis.

T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy

“…We previously reported that in addition to its canonical apoptosis-inducing functions, Fas can also promote mouse and human T cell differentiation in an Akt-dependent manner (58,59). Consistent with these findings, we discovered that T cells transduced with Fas DNRs were protected from lz-FasL-mediated induction of pAkt S473 and pS6 S235,S236 .…”

“…Having established that adoptively transferred T cells engineered with a Fas DNR results in enhanced persistence without long-term toxicity, we next evaluated the antitumor efficacy of these cells. We recently discovered that Fas stimulation can induce non-apoptotic Akt/mTOR signaling, resulting in augmented T cell differentiation (58)(59)(60). Consistent with our previous results, we found that exposure to lz-FasL caused a dose-dependent increase in phosphorylated Akt S473 (pAkt S473 ) and pS6 S235,S236 in T cells transduced with an empty vector control (Supplemental Figure 8, A and B).…”

Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy

“…Expression of multiple costimulatory members of the TNF receptor superfamily linked to enhanced CAR T cell function, such as CD28 and ICOS (46), were also differentially retained by AKTi-treated cells. Conversely, we found that genes associated with acquisition of T cell effector functions, including the cytotoxic proteases GZMA, GZMB, GZMH, and GZMM and the death/differentiation-inducing ligand FASLG (21,55,56), were suppressed by AKT inhibition. Moreover, genes involved in apoptosis induction, such as BAD, BAX, and TRAIL, were also downregulated.…”

Cell-cell contact dictates life or death decisions following CD95 activation in cancer

“…The evolution of CD95 clusters was found to scale with apoptosis induction in a similar manner. Recent PALM imaging confirmed the existence of CD95 clusters and showed their dependence on palmitoylation of CD95 for lipid-raft localization (24). A rigid-body based computational model of membrane receptor-ligand interactions further illustrated that confining the structural flexibility of receptors via membrane topology has an influence on the binding to its ligand (25).…”