Vella, G. | Search bioRxiv

bioRxiv2025

Autophagy maintains HEV identity and function during inflammation

High endothelial venules (HEVs) play a crucial role in adaptive immune responses in secondary and tertiary lymphoid organs. They are uniquely equipped with high levels of peripheral node addressins (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 maintaining HEVs remain underexplored. Here, we report that autophagy is essential for HEV function and expansion. Using single-cell transcriptomics, intravital imaging, and an inducible HEV tracer system in mice, we demonstrate that autophagy deficiency compromises LT{beta}R-signaling and the Unfolded Protein Response in HEVs, leading to disrupted PNAd production, dedifferentiation, and reduced lymphocyte homing. Autophagy deficiency and LT{beta}R blockade impaired HEV function and reduced skin inflammation in psoriasis-bearing mice by limiting immune infiltration and cytokine release. Our work uncovers an unprecedented role of autophagy in safeguarding HEV identity and function during inflammation. HighlightsO_LIHigh endothelial venules (HEVs) exhibit heightened autophagy in comparison to non-HEV blood endothelial cells, which further increases during inflammation. C_LIO_LIAutophagy is pivotal in maintaining HEV fate and function, specifically during inflammation, via LT{beta}R signaling and the Unfolded Protein Response (UPR), ensuring the proper production of peripheral node addressins (PNAd) that serve as L-selectin ligands for the efficient influx of naive lymphocytes. C_LIO_LIBlocking autophagy in HEVs leads to disrupted PNAd production, HEV flattening and dedifferentiation, and reduced lymphocyte homing. C_LIO_LIGenetic and pharmacological perturbation of HEV function in the lymph nodes and skin lesions of psoriasis-bearing mice impaired neutrophil and lymphocyte recruitment, as well as cytokine secretion, thereby alleviating skin inflammation. C_LI

cell biology↗

bioRxiv2021

Anticancer immunotherapies transition postcapillary venules into high-endothelial venules that generate TCF1+ T lymphocyte niches through a feed-forward loop

The lack of T-cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLS), which are the local site of humoral and cellular immune responses against cancers, are associated with good prognosis and have recently been detected in Immune Checkpoint Blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing scRNA sequencing, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke the transition of postcapillary venules into inflamed high endothelial venules (HEVs), which generate permissive TA-TLS-like lymphocyte niches with PD1neg and PD1+TCF1+CD8 T cell progenitors that differentiate into GrzB+TCF1neg TIM3+ PD1+ CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived lymphotoxin signals revealing that tumor-HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop. In BriefHua & Vella et al. reveal that effective antiangiogenic immunotherapy transitions postcapillary venules into inflamed high-endothelial venules (HEV), sustained by CD8 T and NK cell-derived signals through a feed-forward loop. Thereby, tumoral HEVs establish perivascular niches in which TCF1+ PD1+ lymphocytes expand and produce cytolytic PD1+ TIM3+ CD8 T cells that facilitate anti-tumoral immunity. HighlightsO_LIHigh endothelial venule induction by anticancer immunotherapies generates perivascular immune niches permissive for TCF1+ PD1+ CD8 progenitor T cell expansion and production of TCF1neg PD1+ TIM3+ CD8 effector T cells C_LIO_LITumoral high-endothelial venules exhibit characteristics of inflamed lymph node HEVs and postcapillary venules C_LIO_LIPostcapillary venules dynamically transdifferentiate into high-endothelial venules in tumors, which requires continuous signals from surrounding immune cells C_LIO_LICD8 and NK cells drive tumoral high-endothelial venule formation during antiangiogenic immunotherapies in a feed-forward loop via lymphotoxin beta receptor signaling C_LI

cancer biology↗