title: Direct activation of antigen-presenting cells is required for CD8+ T-cell priming and tumor vaccination.
abstract: Successful priming of adaptive immune responses is crucially dependent on innate activation signals that convert resting antigen-presenting cells (APCs) into immunogenic ones. APCs expressing the relevant innate pattern recognition receptors can be directly activated by pathogen-associated molecular patterns (PAMPs) to become competent to prime T-cell responses. Alternatively, it has been suggested that APCs could be activated indirectly by proinflammatory mediators synthesized by PAMP-exposed cells. However, data obtained with CD4(+) T cells suggest that inflammatory signals often cannot substitute for direct pattern recognition in APC activation for the priming of T helper responses. To test whether the same is true for CD8(+) T cells, we studied cytotoxic T lymphocyte development in vitro and in mixed chimeric mice in which coexisting APCs can either present a preprocessed model antigen or directly recognize a given PAMP, but not both. We show that indirectly activated APCs promote antigen-specific proliferation of naïve CD8(+) T cells but fail to support their survival and cytotoxic T lymphocyte differentiation. Furthermore, CD8(+) T cells primed by indirectly activated APCs are unable to reject tumors. Thus, inflammation cannot substitute for direct recognition of single PAMPs in CD8(+) T-cell priming. These findings have important practical implications for vaccine design, indicating that adjuvants must be judiciously chosen to trigger the relevant pattern recognition receptors in APCs.
authors: Institute for Microbiology, Eidgenössische Technische Hochschule Zürich, 8093 Zürich, Switzerland.
authors: Wolfgang
authors: W
authors: Kratky
authors: Caetano
authors: C
authors: Reis e Sousa
authors: Annette
authors: A
authors: Oxenius
authors: Roman
authors: R
authors: Spörri
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D005260:Female; D007113:Immunity, Innate; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011828:Radiation Chimera; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology
chemical_list: D019496:Cancer Vaccines