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      CD11b +Ly6C ++Ly6G - Cells with Suppressive Activity Towards T Cells Accumulate in Lungs of Influenza a Virus-Infected Mice

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          Influenza A virus (IAV) infection causes an acute respiratory disease characterized by a strong inflammatory immune response and severe immunopathology. Proinflammatory mechanisms are well described in the murine IAV infection model, but less is known about the mechanisms leading to the resolution of inflammation. Here, we analyzed the contribution of CD11b +Ly6C ++Ly6G cells to this process. An accumulation of CD11b +Ly6C ++Ly6G cells within the lungs was observed during the course of IAV infection. Phenotypic characterization of these CD11b +Ly6C ++Ly6G cells by flow cytometry and RNA-Seq revealed an activated phenotype showing both pro- and anti-inflammatory features, including the expression of inducible nitric oxide synthase (iNOS) by a fraction of cells in an IFN-γ-dependent manner. Moreover, CD11b +Ly6C ++Ly6G cells isolated from lungs of IAV-infected animals displayed suppressive activity when tested in vitro, and iNOS inhibitors could abrogate this suppressive activity. Collectively, our data suggest that during IAV infection, CD11b +Ly6C ++Ly6G cells acquire immunoregulatory function, which might contribute to the prevention of pathology during this life-threatening disease.

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          Most cited references 37

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          Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer.

          Antigen-specific CD8+ T-cell tolerance, induced by myeloid-derived suppressor cells (MDSCs), is one of the main mechanisms of tumor escape. Using in vivo models, we show here that MDSCs directly disrupt the binding of specific peptide-major histocompatibility complex (pMHC) dimers to CD8-expressing T cells through nitration of tyrosines in a T-cell receptor (TCR)-CD8 complex. This process makes CD8-expressing T cells unable to bind pMHC and to respond to the specific peptide, although they retain their ability to respond to nonspecific stimulation. Nitration of TCR-CD8 is induced by MDSCs through hyperproduction of reactive oxygen species and peroxynitrite during direct cell-cell contact. Molecular modeling suggests specific sites of nitration that might affect the conformational flexibility of TCR-CD8 and its interaction with pMHC. These data identify a previously unknown mechanism of T-cell tolerance in cancer that is also pertinent to many pathological conditions associated with accumulation of MDSCs.
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            Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10

            Activated antigen-specific T cells produce a variety of effector molecules for clearing infection, but also contribute significantly to inflammation and tissue injury. Here we report an anti-inflammatory property of anti-viral CD8+ and CD4+ effector T cells (Te) in the infected periphery during acute virus infection. We find that, during acute influenza infection, IL-10 is produced in the infected lungs at high levels -- exclusively by infiltrating virus-specific Te, with CD8+ Te contributing a larger fraction of the IL-10 produced. These Te in the periphery simultaneously produce IL-10 and proinflammatory cytokines, and express lineage markers characteristic of conventional Th/c1 cells. Importantly, blocking the action of the Te-derived IL-10 results in enhanced pulmonary inflammation and lethal injury. Our results demonstrate that anti-viral Te exert regulatory functions -- that is, fine-tune the extent of lung inflammation and injury associated with influenza infection by the production of an anti-inflammatory cytokine. The potential implications of these findings for infection with highly pathogenic influenza viruses are discussed.
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              TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection.

              Respiratory infection with highly pathogenic influenza A viruses is characterized by the exuberant production of cytokines and chemokines and the enhanced recruitment of innate inflammatory cells. Here, we show that challenging mice with virulent influenza A viruses, including currently circulating H5N1 strains, causes the increased selective accumulation of a particular dendritic cell subset, the tipDCs, in the pneumonic airways. These tipDCs are required for the further proliferation of influenza-specific CD8(+) T cells in the infected lung, because blocking their recruitment in CCR2(-/-) mice decreases the numbers of CD8(+) effectors and ultimately compromises virus clearance. However, diminution rather than total elimination of tipDC trafficking by treatment with the peroxisome proliferator-activated receptor-gamma agonist pioglitazone moderates the potentially lethal consequences of excessive tipDC recruitment without abrogating CD8(+) T cell expansion or compromising virus control. Targeting the tipDCs in this way thus offers possibilities for therapeutic intervention in the face of a catastrophic pandemic.

                Author and article information

                Eur J Microbiol Immunol (Bp)
                Eur J Microbiol Immunol (Bp)
                European Journal of Microbiology & Immunology
                Akadémiai Kiadó (Budapest )
                04 November 2015
                December 2015
                : 5
                : 4
                : 246-255
                [1 ] Department of Experimental Immunology, Helmholtz Centre for Infection Research , Braunschweig, Germany
                [2 ]Genomics and Immunoregulation, LIMES – Institute, University of Bonn , Bonn, Germany
                [3 ]Institute for Laboratory Animal Science, Hannover Medical School , Hannover, Germany
                [4 ] Department of Infection Genetics, Helmholtz Centre for Infection Research , Braunschweig, Germany, University of Veterinary Medicine Hannover, University of Tennessee Health Science Center , Memphis, USA
                [5 ]Institute of Virology and Immunobiology, University of Würzburg , Würzburg, Germany
                Author notes
                * Inhoffenstraße 7, 38124 Braunschweig, Germany; +49 531 6181 3310+49 531 6181 3399; Jochen.Huehn@
                + Present address: Laboratory of Systems Biology, National Institute of Health, Bethesda, USA

                Conflict of interest disclosure

                The authors declare no financial or commercial conflict of interest.

                © 2015, The Author(s)

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 9, Tables: 0, Equations: 0, References: 39, Pages: 12
                Original Article


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