New research that our group was involved in is now out at BioRxiv, where we helped determine the nanoscale architecture of the NLRP3 inflammasome. www.biorxiv.org/content/10.6...

Overall, our study shows that TIGIT signalling is logic gated. This reveals a regulatory element controlling checkpoint signalling, limiting its activity to the precise moment a T cell is being activated. www.cell.com/cell-reports...

Mechanistically, TIGIT phosphorylation and subsequent internalisation required both CD155 ligation and TCR activation. This means TIGIT signalling depends on the activation state of the T cell. (8/9)

By comparing the proximity proteome of ligated TIGIT with or without TCR stimulation, we saw that the CD155-ligated and signalling-dependent TIGIT-proximal proteins also required TCR stimulation to be recruited. (6/9)

Previously, using nanoscopy, we demonstrated that TIGIT clusters upon ligation, which coalesce with TCR clusters. As many of the proximity proteomics hits could be indistinguishable from a TCR signalosome, we sought to differentiate the two. (5/9)

We next asked whether TIGIT’s cytoplasmic signalling motifs were needed to recruit these pathways. A TIGIT mutant, Y225A/Y231A, incapable of inhibitory signalling, failed to recruit the identified proteins. (4/9)

The identified TIGIT-proximal proteins specifically enriched after ligand engagement were linked to signalling (i.e. Grb2, SOS1), cytoskeletal regulation (CD2AP and SdcBP) and endocytosis (IST1 and SNX3). (3/9)

To study this, we used proximity proteomics to map the TIGIT signalosome upon engagement with its ligand CD155 in T cells. This allowed us to ask what pathways TIGIT recruits upon ligation. (2/9)

Delighted to have visited the Dept. of Pathology at the University of Cambridge today to present our work. Some fantastic discussions!