The immune system differentiates self from nonself through the display of antigens on the cellular surface in association with class I major histocompatibility complex (MHC) molecules. Although the basic principle of immune peptide presentation by the MHC class I system is well understood, the exact provenance of the peptides used in this pathway remains poorly defined. Building on their previous work demonstrating that the pioneer round of mRNA translation is a major source of antigenic peptide substrates, Fåhraeus and colleagues now show that prespliced RNAs—translated in the nucleus through a noncanonical mechanism—can be a source of peptides for the MHC class I pathway. To detect early ribosomal scanning events that give rise to antigenic peptide products, the authors engineered constructs for expression of exogenous antigenic peptides from intronic sequences within the β-globin gene and confirmed that the mRNAs' presence within the cell was limited to the nuclear compartment. The presentation of the antigenic peptides was reduced by ∼100 fold when their gene sequences were placed in a reading frame different from that of the host gene, thus indicating that the peptides are the translation products of unspliced mRNAs. Because the unspliced reporter mRNA was restricted to the nucleus, the authors surmised that the synthesis of pioneer translation products for the MHC class I pathway must occur within this compartment. Accordingly, forcing export of the unspliced construct by fusion with the HIV REV element reduced antigen presentation. Finally, the authors could detect the colocalization of nascent peptide products and ribosomal proteins within the nucleus, confirming active nuclear translation. Although the existence and possible function of nuclear translation have been controversial, the new findings described here provide evidence for nuclear ribosomes being part of a specialized translation system that is key to immune surveillance. (Proc. Natl. Acad. Sci. USA 110, 17951–17956, 2013)