Conventional type 1 dendritic cells (cDC1s) are inherently resistant to many viruses but, paradoxically, possess fewer acidic phagosomes that enable antigen retention and cross-presentation. We report that palmitoyl-protein thioesterase 1 (PPT1), which catabolizes lipid-modified proteins in neurons, is highly expressed in cDC1s. PPT1-deficient DCs are more susceptible to vesicular stomatitis virus (VSV) infection, and mice with PPT1 deficiency in cDC1s show impaired response to VSV. Conversely, PPT1-deficient cDC1s enhance the priming of naive CD8+ T cells into tissue-resident KLRG1+ effectors and memory T cells, resulting in rapid clearance of tumors and Listeria monocytogenes. Mechanistically, PPT1 protects steady state DCs from viruses by promoting antigen degradation and endosomal acidification via V-ATPase recruitment. After DC activation, immediate down-regulation of PPT1 is likely to facilitate efficient cross-presentation, production of costimulatory molecules and inflammatory cytokines. Thus, PPT1 acts as a molecular rheostat that allows cDC1s to crossprime efficiently without compromising viral resistance. These results suggest potential therapeutics to enhance cDC1-dependent crosspriming.

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