Publication: Fas acts as a T cell co-stimulatory receptor both via a death domain-independent and dependent mechanism

Publié dans: 2025

Auteurs: Aurélie Rossin, Giorgia Miloro, Laurent Gagnoux-Palacios, Sebastien Huault, Agnès Loubat, Anthony Formisano, Xiao-Jun Guo, Hai-Tao He, Anne-Odile Hueber

Résumé

T cell responses are regulated by co-stimulatory and inhibitory signalling pathways, driven by receptors and their ligands designated as immune checkpoints. These receptors belong either to the immunoglobulin superfamily or the tumour necrosis factor receptor (TNFR) superfamily. Despite their crucial role in enhancing T effector cell activity, the molecular mechanisms triggered by TNFR costimulatory receptors, particularly their integration into the T cell receptor (TCR) signalling network, remain incompletely characterized. The receptor Fas is classically recognized as the prototypical TNFR death receptor due to the presence of an intracellular death domain (DD). While best known for its ability to trigger cell death, Fas has also been involved in non-death functions, including T cell co-stimulation. Despite its key role in dictating T cell fate, only few studies have explored its involvement as a TCR costimulatory receptor and the underlying molecular mechanisms have not been solved. We show here that Fas constitutively concentrates in plasma membrane domains at the immune synapse where it can be activated by antigen-presenting cell (APC) membrane-anchored FasL. This proximity to the TCR signalling molecules allows Fas, in a DD-independent manner, to lower the TCR activation threshold thereby enhancing the number of activated cells. Additionally, Fas triggers a DD-dependent signaling cascade composed of FADD, caspase-8 and RIPK1, ultimately leading to TAK1 activation. TAK1 in turn initiates gene-activating signalling pathways essential for a complete Fas co-stimulatory response.Moreover, we identified the catalytic activity of caspase-8 as a tipping point in Fas signalling during TCR co-stimulation. Indeed, inhibiting caspase 8 not only prevents cell death but also promotes T cell costimulation by favoring RIPK1-dependent signalling. Altogether, our findings reveal a complex mechanism by which Fas integrates at multiple levels of the TCR spatial organization and signalling network, synergizing with TCR signalling to achieve full T cell activation.

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