Channeling antigens to CD8+ T cells

Cytotoxic CD8+ T cells (CTLs) can kill any virus-infected cell or tumor cell, providing they display antigenic peptides on major histocompatibility complex class I (MHC-I) molecules. However, tumor cells or virus-infected cells cannot present antigens in a sufficiently stimulating manner to also prime naïve CD8+ T cells to become CTLs. This is the role of conventional dendritic cells (cDCs), which bridge innate and adaptive immunity by capturing exogenous cell-associated antigens on MHC-I molecules and presenting them to naïve CD8+ T cells, while also providing co-stimulation (1). This process is called cross-presentation (2). Despite the importance of cross-presentation for antitumor and antiviral immunity and vaccine design, the mechanisms remain unclear. On page 1258 of this issue, Rodríguez-Silvestre et al. (3) report that endosomal perforin-2 is a channel-forming protein that allows the release of internalized exogenous cell-associated antigens to the cytosol of cross-presenting cDCs. © 2023 American Association for the Advancement of Science. All rights reserved.