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      Towards Future T Cell-Mediated Influenza Vaccines

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          Abstract

          Influenza A virus infections (IAVs) impact significantly on global health, being particularly problematic in children, the elderly, pregnant women, indigenous populations and people with co-morbidities. Antibody-based vaccines require annual administration to combat rapidly acquired mutations modifying the surface haemagglutinin (HA) and neuraminidase (NA) glycoproteins. Conversely, influenza-specific CD8 + T cell responses directed at peptides derived from the more conserved internal virus proteins are known to be protective, suggesting that T cell-based vaccines may provide long-lasting cross-protection. This review outlines the importance of CD8 + T cell immunity to seasonal influenza and pandemic IAVs and summarises current vaccination strategies for inducing durable CD8 + T cell memory. Aspectsof future IAV vaccine design and the useof live virus challenge in humans to establish proof of principle are also discussed.

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          Most cited references74

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          Human Infection with a Novel Avian-Origin Influenza A (H7N9) Virus

          New England Journal of Medicine, 368(20), 1888-1897
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            In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens.

            Cytotoxic T lymphocytes (CTL) respond to antigenic peptides presented on MHC class I molecules. On most cells, these peptides are exclusively of endogenous, cytosolic origin. Bone marrow-derived antigen-presenting cells, however, harbor a unique pathway for MHC I presentation of exogenous antigens. This mechanism permits cross-presentation of pathogen-infected cells and the priming of CTL responses against intracellular microbial infections. Here, we report a novel diphtheria toxin-based system that allows the inducible, short-term ablation of dendritic cells (DC) in vivo. We show that in vivo DC are required to cross-prime CTL precursors. Our results thus define a unique in vivo role of DC, i.e., the sensitization of the immune system for cell-associated antigens. DC-depleted mice fail to mount CTL responses to infection with the intracellular bacterium Listeria monocytogenes and the rodent malaria parasite Plasmodium yoelii.
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              T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions.

              Although in vivo priming of CD8+ cytotoxic T lymphocytes (CTLs) generally requires the participation of CD4+ T-helper lymphocytes, the nature of the 'help' provided to CTLs is unknown. One widely held view is that help for CTLs is mediated by cytokines produced by T-helper cells activated in proximity to the CTL precursor at the surface of an antigen-presenting cell (APC). An alternative theory is that, rather than being directly supplied to the CTL by the helper cell, help is delivered through activation of the APC, which can then prime the CTL directly. CD40 and its ligand, CD40L, may activate the APC to allow CTL priming. CD40L is expressed on the surface of activated CD4+ T-helper cells and is involved in their activation and in the development of their effector functions. Ligation of CD40 on the surface of APCs such as dendritic cells, macrophages and B cells greatly increases their antigen-presentation and co-stimulatory capacity. Here we report that signalling through CD40 can replace CD4+ T-helper cells in priming of helper-dependent CD8+ CTL responses. Blockade of CD40L inhibits CTL priming; this inhibition is overcome by signalling through CD40. CD40-CD40L interactions are therefore vital in the delivery of T-cell help for CTL priming.
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                Author and article information

                Contributors
                Journal
                Infectious Diseases and Translational Medicine
                Infect. Dis. Transl. Med.
                Infect. Dis. Transl. Med.
                International Biological and Medical Journals Publishing House Co., Limited (Room E16, 3/f, Yongda Commercial Building, No.97, Bonham Stand (Sheung Wan), HongKong )
                2411-2917
                10 April 2016
                10 April 2016
                : 2
                : 1
                : 20-29
                Affiliations
                From the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville 3010, Victoria, Australia
                From the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville 3010, Victoria, Australia
                From the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville 3010, Victoria, Australia
                From the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville 3010, Victoria, Australia; Department of Immunology, St Jude Children’s Research Hospital, Memphis, Tennesse 38105, USA
                From the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville 3010, Victoria, Australia
                Author notes
                Correspondence to: Associate Professor Katherine Kedzierska, Department of Microbiology & Immunology, University of Melbourne, The Peter Doherty Institute for Infection & Immunity, Level 7, 792 Elizabeth Street, Melbourne, 3000, VIC Australia. Email: kkedz@ 123456unimelb.edu.au .
                Article
                10.11979/idtm.201601004
                a3ae416f-3010-4f5f-8cf1-9747f11d66bf

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                Page count
                Figures: 2, Tables: 0, References: 91, Pages: 10
                Product
                Categories
                Review

                Medicine,Infectious disease & Microbiology
                Vaccines,T cells,Influenza viruses
                Medicine, Infectious disease & Microbiology
                Vaccines, T cells, Influenza viruses

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