Blander J Magarian, Medzhitov Ruslan
Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, 300 Cedar Street, New Haven, Connecticut 06520, USA.
Nature. 2006 Apr 6;440(7085):808-12. doi: 10.1038/nature04596. Epub 2006 Feb 19.
Dendritic cells constitutively sample the tissue microenvironment and phagocytose both microbial and host apoptotic cells. This leads to the induction of immunity against invading pathogens or tolerance to peripheral self antigens, respectively. The outcome of antigen presentation by dendritic cells depends on their activation status, such that Toll-like receptor (TLR)-induced dendritic cell activation makes them immunogenic, whereas steady-state presentation of self antigens leads to tolerance. TLR-inducible expression of co-stimulatory signals is one of the mechanisms of self/non-self discrimination. However, it is unclear whether or how the inducible expression of co-stimulatory signals would distinguish between self antigens and microbial antigens when both are encountered by dendritic cells during infection. Here we describe a new mechanism of antigen selection in dendritic cells for presentation by major histocompatibility complex class II molecules (MHC II) that is based on the origin of the antigen. We show that the efficiency of presenting antigens from phagocytosed cargo is dependent on the presence of TLR ligands within the cargo. Furthermore, we show that the generation of peptide-MHC class II complexes is controlled by TLRs in a strictly phagosome-autonomous manner.
树突状细胞持续监测组织微环境，并吞噬微生物和宿主凋亡细胞。这分别导致针对入侵病原体的免疫诱导或对外周自身抗原的耐受。树突状细胞提呈抗原的结果取决于其激活状态，例如Toll样受体（TLR）诱导的树突状细胞激活使其具有免疫原性，而自身抗原的稳态提呈则导致耐受。共刺激信号的TLR诱导性表达是自我/非自我识别的机制之一。然而，尚不清楚当树突状细胞在感染期间同时遇到自身抗原和微生物抗原时，共刺激信号的诱导性表达是否以及如何区分它们。在此，我们描述了一种基于抗原来源的树突状细胞中主要组织相容性复合体II类分子（MHC II）提呈抗原选择的新机制。我们表明，提呈来自吞噬货物中抗原的效率取决于货物中TLR配体的存在。此外，我们表明肽-MHC II类复合物的产生以严格的吞噬体自主方式受TLR控制。
