Beyond Cell Death: New Functions for TNF Family Cytokines in Autoimmunity and Tumor Immunotherapy

Abstract

Originally discovered as an inducer of apoptosis, the TNF-family receptor Fas (CD95, APO-1, TNFRSF6) has more recently been found to have functions beyond cell death, including T cell co-stimulation and promoting terminal differentiation of CD4 and CD8 T cells. Other TNF family members also discovered as apoptosis inducers, such as TRAIL (APO-2L, TNFSF10), can promote inflammation through caspase-8. Surprisingly, non-apoptotic signaling through Fas can protect from the autoimmunity seen in Fas deficiency independently from the cell death inducing functions of the receptor. Non-apoptotic Fas signaling can induce tumor cell growth and migration, and impair the efficacy of T cell adoptive immunotherapy. Blocking of non-apoptotic functions of these receptors may be a novel strategy to regulate autoimmunity and inflammation, and enhance antitumor immunity.

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

“…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).…”

Myelin-specific CD8+ T cells exacerbate brain inflammation in CNS autoimmunity

“…We then investigated whether FasL expression by 8.8 CD8 + T cells was required for the enhanced ROS production by MdCs and monocytes, as Fas signaling has been shown to activate these cell types to produce proinflammatory mediators (41)(42)(43)(44). Importantly, MdCs in the brains of mice that received FasL gld 8.8 CD8 + T cells failed to upregulate ROS production ( Figure 6, E and F).…”

TNFPred: Identifying tumor necrosis factors using hybrid features based on word embeddings

“…Among major families of cytokines (interleukins (IL), interferons (IFNs), tumor necrosis factors (TNFs), chemokine and various growth factors, comprised of transforminggrowth factor b(TGF-b), fibroblast growth factor (FGF), heparin binding growth factor (HBGF) and neuron growth factor (NGF)) [1], tumor necrosis factors are versatile cytokines with a wide range of functions that attracts abundant of biological researchers (see, e.g. [2][3][4][5][6]). TNFs can take part in pathological reactions as well as involve in a variety of processes, such as inflammation, tumor growth, transplant rejection, etc.…”