Fas cell surface death receptor (Fas) and Fas ligand (FasL) pathway (Fas/FasL pathway)

The Fas-FasL pathway, consisting of the Fas cell surface death receptor (CD95) and its cognate Fas ligand (FasL/CD178), is a fundamental mediator of the extrinsic apoptotic pathway and immune system homeostasis [1, 2]. In the context of alloreactive T cells, such as those involved in Graft-versus-Host Disease (GvHD) or organ transplant rejection, this pathway serves as a primary mechanism for T-cell mediated cytotoxicity against host tissues [3, 4]. Conversely, the interaction is also responsible for activation-induced cell death (AICD), which serves to terminate immune responses by eliminating activated T cells [3]. Therapeutic strategies targeting this pathway in alloreactive T cells aim to either block FasL-mediated tissue destruction using decoy receptors like Asunercept or to induce apoptosis in the alloreactive T cells themselves using Fas agonists [5]. However, the clinical application of Fas-targeted therapies is severely limited by the risk of profound hepatotoxicity, as hepatocytes are highly susceptible to Fas-mediated death [3, 4]. Current drug development efforts focus on achieving cell-specific or localized modulation to mitigate these systemic safety concerns [5].

Other names

CD95/CD178 pathwayAPO-1/FasL axisTNFRSF6/TNFSF6 pathwayDeath receptor pathwayExtrinsic apoptotic pathway

Modulation of the extrinsic apoptotic pathway through either the inhibition of Fas-FasL binding to protect host tissues or the activation of Fas signaling to eliminate alloreactive T cells [4, 5].