Autophagy maintains high endothelial venule identity and function during inflammation.

High endothelial venules (HEVs) play a crucial role in adaptive immune responses in secondary lymphoid organs (SLOs). They are equipped with high amounts of peripheral node addressin (PNAd), harboring carbohydrate structures that serve as L-selectin ligands to efficiently facilitate lymphocyte homing. During inflammation, the HEV network expands in SLOs, increasing lymphocyte infiltration, but the underlying mechanisms that maintain HEVs remain underexplored. Here, we report that autophagy is essential for HEV function and expansion. Using single-cell transcriptomics, unbiased proteomics, intravital imaging, and an inducible HEV tracer system in mice, we demonstrate that autophagy deficiency compromises lymphotoxin beta receptor (LTβR) signaling and the unfolded protein response in HEVs, leading to disrupted PNAd production, dedifferentiation, and reduced lymphocyte homing. Autophagy deficiency and LTβR blockade impair HEV function and reduce skin inflammation in psoriasis-affected mice by limiting immune infiltration and cytokine release. Our work reveals that autophagy safeguards HEV identity and function during inflammation.