VPS33B regulates MHC class II antigen presentation in dendritic cells to drive CD4 T cell immunity.

Vacuolar protein sorting-associated protein (VPS)33B is essential for endosomal-lysosomal fusion, with its dysfunction linked to arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome. VPS33B has been implicated in mediating Toll-like receptor degradation in macrophages, a critical step to mitigate inflammation. Here, we uncover a pivotal function of VPS33B in dendritic cell (DC)-mediated antigen presentation. Loss of VPS33B in DCs impairs peptide-MHC class II presentation, leading to diminished CD4 T cell responses. Absence of VPS33B selectively compromises CD4-dependent CD8 T cell responses while not impacting CD4-independent CD8 T cell priming, indicating that VPS33B only affects the MHC class II pathway. Mechanistically, we find that VPS33B is required for optimal presentation of MHC class II-associated peptides as VPS33B-deficient DCs predominantly express MHC class II loaded with invariant chain degradation intermediates. Our work highlights VPS33B as a key regulator of antigen presentation and underscores its importance in orchestrating CD4 T cell-mediated immunity.