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Summary
For the adaptive immune system to detect intracellular infection, microbial protein fragments (antigens) must be presented by major histocompatibility complex class I (MHC-I) molecules. This entails an elaborate intracellular folding of MHC-I molecules with peptides from the infecting pathogen, followed by their display on the cell surface for surveillance by CD8+ T cells (1). In a variation of this classical pathway of MHC-I antigen presentation, a subset of professional antigen-presenting cells called dendritic cells (DCs) conduct cross-presentation, whereby MHC-I molecules are directed to present exogenous peptides from internalized microbes and dying infected cells or cancer cells (2). Because of the potential to prime cytotoxic CD8+ T cells against intracellular pathogens and cancer cells, cross-presentation has preoccupied immunologists for decades. But how this process is orchestrated remains poorly understood. On page 694 of this issue, Theisen et al. (3) reveal a critical role for the protein WDFY4 (WD repeat- and FYVE domain–containing protein 4) in cross-presentation and not in classical MHC-I antigen presentation. The authors show that WDFY4 works specifically in the conventional DC1 (cDC1) subset and is responsible for their specialization at cross-presentation (4). This revelation identifies WDFY4 as a therapeutic target to mobilize cytotoxic CD8+ T cells against tumors and infected cells.
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