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      Notch2-dependent classical dendritic cells orchestrate intestinal immunity against attaching and effacing bacterial pathogens

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          Abstract

          Defense against attaching and effacing (A/E) bacteria requires the sequential generation of interleukin 23 (IL-23) and IL-22 to induce protective mucosal responses. While CD4 + and NKp46 + innate lymphoid cells (ILCs) are the critical source of IL-22 during infection, the precise source of IL-23 is unclear. We used genetic techniques to deplete specific subsets of classical dendritic cells (cDCs) and analyzed immunity to the A/E pathogen Citrobacter rodentium. We found that Notch2 controlled the terminal stage of cDC differentiation. Notch2-dependent intestinal CD11b + cDCs, but not Batf3-dependent CD103 + cDCs, were an obligate source of IL-23 required to survive C. rodentium infection. These results provide the first demonstration of a non-redundant function of CD11b + cDCs in response to pathogens in vivo.

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          Most cited references45

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          Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity.

          Although in vitro observations suggest that cross-presentation of antigens is mediated primarily by CD8alpha+ dendritic cells, in vivo analysis has been hampered by the lack of systems that selectively eliminate this cell lineage. We show that deletion of the transcription factor Batf3 ablated development of CD8alpha+ dendritic cells, allowing us to examine their role in immunity in vivo. Dendritic cells from Batf3-/- mice were defective in cross-presentation, and Batf3-/- mice lacked virus-specific CD8+ T cell responses to West Nile virus. Importantly, rejection of highly immunogenic syngeneic tumors was impaired in Batf3-/- mice. These results suggest an important role for CD8alpha+ dendritic cells and cross-presentation in responses to viruses and in tumor rejection.
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            Decisions about dendritic cells: past, present, and future.

            A properly functioning adaptive immune system signifies the best features of life. It is diverse beyond compare, tolerant without fail, and capable of behaving appropriately with a myriad of infections and other challenges. Dendritic cells are required to explain how this remarkable system is energized and directed. I frame this article in terms of the major decisions that my colleagues and I have made in dendritic cell science and some of the guiding themes at the time the decisions were made. As a result of progress worldwide, there is now evidence of a central role for dendritic cells in initiating antigen-specific immunity and tolerance. The in vivo distribution and development of a previously unrecognized white cell lineage is better understood, as is the importance of dendritic cell maturation to link innate and adaptive immunity in response to many stimuli. Our current focus is on antigen uptake receptors on dendritic cells. These receptors enable experiments involving selective targeting of antigens in situ and new approaches to vaccine design in preclinical and clinical systems.
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              Differential antigen processing by dendritic cell subsets in vivo.

              Dendritic cells (DCs) process and present self and foreign antigens to induce tolerance or immunity. In vitro models suggest that induction of immunity is controlled by regulating the presentation of antigen, but little is known about how DCs control antigen presentation in vivo. To examine antigen processing and presentation in vivo, we specifically targeted antigens to two major subsets of DCs by using chimeric monoclonal antibodies. Unlike CD8+ DCs that express the cell surface protein CD205, CD8- DCs, which are positive for the 33D1 antigen, are specialized for presentation on major histocompatibility complex (MHC) class II. This difference in antigen processing is intrinsic to the DC subsets and is associated with increased expression of proteins involved in MHC processing.
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                Author and article information

                Journal
                100941354
                21750
                Nat Immunol
                Nat. Immunol.
                Nature immunology
                1529-2908
                1529-2916
                14 September 2013
                04 August 2013
                September 2013
                01 March 2014
                : 14
                : 9
                : 937-948
                Affiliations
                [1 ]Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA
                [2 ]Howard Hughes Medical Institute, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA
                [3 ]Department of Immunology, University of Toronto, Toronto, Ontario, Canada
                [4 ]Department of Developmental Biology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA
                [5 ]Department of Internal Medicine, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA
                [6 ]Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, USA
                [7 ]Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
                [8 ]Department of Immunology, Genentech, South San Francisco, California, USA
                [9 ]Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA
                Author notes
                Correspondence should be addressed to K.M.M. ( kmurphy@ 123456wustl.edu ), Phone 314-362-2009, Fax 314-747-4888
                Article
                NIHMS500270
                10.1038/ni.2679
                3788683
                23913046
                480d423b-1c93-4ac8-81fe-88b959280410

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of Dental and Craniofacial Research : NIDCR
                Award ID: R01 DE021255 || DE
                Categories
                Article

                Immunology
                Immunology

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