Autophagy maintains HEV identity and function during inflammation.

During inflammation, the HEV network expands and upregulates additional adhesion molecules for proper T cell influx, but the underlying mechanisms remain poorly understood. Here we report that autophagy is essential for the proper expansion and functioning of HEVs using single-cell transcriptomics, intravital imaging, and novel inducible HEV tracer mouse models.

We demonstrate that lack of autophagy leads to a loss of HEV phenotype and functionality through reduced lymphotoxin beta receptor and Unfolded Protein Response activation, which contribute to decreased production of PNAd. This autophagy-dependent mechanism maintains HEV identity during inflammatory stress. These findings reveal that blocking HEV expansion can be exploited therapeutically, as demonstrated in a psoriasis model where it resulted in less severe disease phenotype.