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      Recalling the Future: Immunological Memory Toward Unpredictable Influenza Viruses

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          Abstract

          Persistent and durable immunological memory forms the basis of any successful vaccination protocol. Generation of pre-existing memory B cell and T cell pools is thus the key for maintaining protective immunity to seasonal, pandemic and avian influenza viruses. Long-lived antibody secreting cells (ASCs) are responsible for maintaining antibody levels in peripheral blood. Generated with CD4 + T help after naïve B cell precursors encounter their cognate antigen, the linked processes of differentiation (including Ig class switching) and proliferation also give rise to memory B cells, which then can change rapidly to ASC status after subsequent influenza encounters. Given that influenza viruses evolve rapidly as a consequence of antibody-driven mutational change (antigenic drift), the current influenza vaccines need to be reformulated frequently and annual vaccination is recommended. Without that process of regular renewal, they provide little protection against “drifted” (particularly H3N2) variants and are mainly ineffective when a novel pandemic (2009 A/H1N1 “swine” flu) strain suddenly emerges. Such limitation of antibody-mediated protection might be circumvented, at least in part, by adding a novel vaccine component that promotes cross-reactive CD8 + T cells specific for conserved viral peptides, presented by widely distributed HLA types. Such “memory” cytotoxic T lymphocytes (CTLs) can rapidly be recalled to CTL effector status. Here, we review how B cells and follicular T cells are elicited following influenza vaccination and how they survive into a long-term memory. We describe how CD8 + CTL memory is established following influenza virus infection, and how a robust CTL recall response can lead to more rapid virus elimination by destroying virus-infected cells, and recovery. Exploiting long-term, cross-reactive CTL against the continuously evolving and unpredictable influenza viruses provides a possible mechanism for preventing a disastrous pandemic comparable to the 1918-1919 H1N1 “Spanish flu,” which killed more than 50 million people worldwide.

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          Most cited references147

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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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            HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells.

            Establishing a CD8(+) T cell-mediated immune correlate of protection in HIV disease is crucial to the development of vaccines designed to generate cell-mediated immunity. Historically, neither the quantity nor breadth of the HIV-specific CD8(+) T-cell response has correlated conclusively with protection. Here, we assess the quality of the HIV-specific CD8(+) T-cell response by measuring 5 CD8(+) T-cell functions (degranulation, IFN-gamma, MIP-1beta, TNF-alpha, and IL-2) simultaneously in chronically HIV-infected individuals and elite nonprogressors. We find that the functional profile of HIV-specific CD8(+) T cells in progressors is limited compared to that of nonprogressors, who consistently maintain highly functional CD8(+) T cells. This limited functionality is independent of HLA type and T-cell memory phenotype, is HIV-specific rather than generalized, and is not effectively restored by therapeutic intervention. Whereas the total HIV-specific CD8(+) T-cell frequency did not correlate with viral load, the frequency and proportion of the HIV-specific T-cell response with highest functionality inversely correlated with viral load in the progressors. Thus, rather than quantity or phenotype, the quality of the CD8(+) T-cell functional response serves as an immune correlate of HIV disease progression and a potential qualifying factor for evaluation of HIV vaccine efficacy.
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              Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major.

              CD4+ T cells have a crucial role in mediating protection against a variety of pathogens through production of specific cytokines. However, substantial heterogeneity in CD4+ T-cell cytokine responses has limited the ability to define an immune correlate of protection after vaccination. Here, using multiparameter flow cytometry to assess the immune responses after immunization, we show that the degree of protection against Leishmania major infection in mice is predicted by the frequency of CD4+ T cells simultaneously producing interferon-gamma, interleukin-2 and tumor necrosis factor. Notably, multifunctional effector cells generated by all vaccines tested are unique in their capacity to produce high amounts of interferon-gamma. These data show that the quality of a CD4+ T-cell cytokine response can be a crucial determinant in whether a vaccine is protective, and may provide a new and useful prospective immune correlate of protection for vaccines based on T-helper type 1 (TH1) cells.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                02 July 2019
                2019
                : 10
                : 1400
                Affiliations
                [1] 1Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne , Melbourne, VIC, Australia
                [2] 2Research Center for Zoonosis Control, Hokkaido University , Sapporo, Japan
                [3] 3WHO Collaborating Centre for Reference and Research on Influenza, Peter Doherty Institute for Infection and Immunity , Melbourne, VIC, Australia
                [4] 4Department of Immunology, St. Jude Children's Research Hospital , Memphis, TN, United States
                Author notes

                Edited by: Nicholas J. Mantis, Wadsworth Center, United States

                Reviewed by: Linda S. Cauley, University of Connecticut Health Center, United States; Shahram Salek-Ardakani, Pfizer, United States

                *Correspondence: Katherine Kedzierska kkedz@ 123456unimelb.edu.au

                This article was submitted to Immunological Memory, a section of the journal Frontiers in Immunology

                †These authors have contributed equally to this work

                Article
                10.3389/fimmu.2019.01400
                6614380
                31312199
                12cc185e-99ff-4331-a59e-005ace9bc7e8
                Copyright © 2019 Auladell, Jia, Hensen, Chua, Fox, Nguyen, Doherty and Kedzierska.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 14 February 2019
                : 03 June 2019
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 230, Pages: 18, Words: 16546
                Funding
                Funded by: National Health and Medical Research Council 10.13039/501100000925
                Categories
                Immunology
                Review

                Immunology
                t cells,b cells,influenza,immunological memory,vaccine
                Immunology
                t cells, b cells, influenza, immunological memory, vaccine

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