Cross-dressed CD8α ⁺ /CD103 ⁺ dendritic cells prime CD8 ⁺ T cells following vaccination

Abstract

Activation of naïve cluster of differentiation (CD)8 + cytotoxic T lymphocytes (CTLs) is a tightly regulated process, and specific dendritic cell (DC) subsets are typically required to activate naive CTLs. Potential pathways for antigen presentation leading to CD8 + T-cell priming include direct presentation, cross-presentation, and cross-dressing. To distinguish between these pathways, we designed single-chain trimer (SCT) peptide-MHC class I complexes that can be recognized as intact molecules but cannot deliver antigen to MHC through conventional antigen processing. We demonstrate that cross-dressing is a robust pathway of antigen presentation following vaccination, capable of efficiently activating both naïve and memory CD8 + T cells and requires CD8α + / CD103 + DCs. Significantly, immune responses induced exclusively by cross-dressing were as strong as those induced exclusively through cross-presentation. Thus, cross-dressing is an important pathway of antigen presentation, with important implications for the study of CD8 + T-cell responses to viral infection, tumors, and vaccines. P rofessional antigen-presenting cells (APCs) are typically required to activate naïve cluster of differentiation (CD)8 + T cells, either by direct priming or cross-priming. In direct priming, infected (viral infection) or directly transfected (DNA vaccination) APCs synthesize the foreign antigen and use endogenous MHC class I pathways of antigen presentation to present antigen and prime CD8 + T cells. In cross-priming, APCs are able to capture, process, and present exogenous antigen onto MHC class I molecules through a process known as cross-presentation (1). Cross-priming has been shown to be an essential pathway for immunity to many viral infections and tumors. Although the pathways that lead to cross-presentation remain incompletely understood, increasing evidence suggests that only certain dendritic cell (DC) subsets are efficient in this process.Cross-dressing involves the transfer of intact MHC class I/ peptide complexes between cells without the requirement for further processing, representing an alternative pathway of indirect antigen presentation (2, 3). Although cross-dressed DCs can activate memory CD8 + T cells following viral infection in vivo (4), it remains unclear whether cross-dressing can prime naïve CD8 + T-cell responses, what DC subtypes are required to prime CD8 + T cells by cross-dressing, and how robust this pathway is compared with traditional pathways of indirect antigen presentation. These questions must be addressed before the physiologic relevance of cross-dressing can be evaluated in context.To address these questions, we have taken advantage of Batf3-deficient mice and engineered MHC class I single chain trimer (SCT) constructs. Batf3 −/− mice have a selective loss of CD8α + and CD103 + DCs, without abnormalities in other hematopoietic cell types or architecture (5). DCs from Batf3 −/− mice are deficient in cross-presentation, and cytotoxic T lymphocyte (CTL) responses to viral infection and synge...

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Membrane Transfer from Tumor Cells Overcomes Deficient Phagocytic Ability of Plasmacytoid Dendritic Cells for the Acquisition and Presentation of Tumor Antigens

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