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During respiratory syncytial virus (RSV) infection CD8+ T cells both assist in viral clearance and contribute to immunopathology. CD8+ T cells recognize viral peptides presented by dendritic cells (DCs), which can directly present viral antigens when infected or, alternatively, "cross-present" antigens after endocytosis of dead or dying infected cells. Mouse CD8α+ and CD103+ DCs excel at cross-presentation, in part because they express the receptor DNGR-1 that detects dead cells by binding to exposed F-actin and routes internalized cell debris into the cross-presentation pathway. As RSV causes death in infected epithelial cells, we tested whether cross-presentation via DNGR-1 is necessary for CD8+ T-cell responses to the virus. DNGR-1-deficient or wild-type mice were intranasally inoculated with RSV and the magnitude of RSV-specific CD8+ T-cell induction was measured. We found that during live RSV infection, cross-presentation via DNGR-1 did not have a major role in the generation of RSV-specific CD8+ T-cell responses. However, after intranasal immunization with dead cells infected with RSV, a dependence on DNGR-1 for RSV-specific CD8+ T-cell responses was observed, confirming the ascribed role of the receptor. Thus, direct presentation by DCs may be the major pathway initiating CD8+ T-cell responses to RSV, while DNGR-1-dependent cross-presentation has no detectable role. [ABSTRACT FROM AUTHOR]