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      Polyfunctional CD4 + T Cells As Targets for Tuberculosis Vaccination

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          Abstract

          Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of morbidity and mortality worldwide, despite the widespread use of the only licensed vaccine, Bacille Calmette Guerin (BCG). Eradication of TB will require a more effective vaccine, yet evaluation of new vaccine candidates is hampered by lack of defined correlates of protection. Animal and human studies of intracellular pathogens have extensively evaluated polyfunctional CD4 + T cells producing multiple pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-2) as a possible correlate of protection from infection and disease. In this study, we review the published literature that evaluates whether or not BCG and/or novel TB vaccine candidates induce polyfunctional CD4 + T cells and if these T cell responses correlate with vaccine-mediated protection. Ample evidence suggests that BCG and several novel vaccine candidates evaluated in animal models and humans induce polyfunctional CD4 + T cells. However, while a number of studies utilizing the mouse TB model support that polyfunctional CD4 + T cells are associated with vaccine-induced protection, other studies in mouse and human infants demonstrate no correlation between these T cell responses and protection. We conclude that induction of polyfunctional CD4 + T cells is certainly not sufficient and may not even be necessary to mediate protection and suggest that other functional attributes, such as additional effector functions, T cell differentiation state, tissue homing potential, or long-term survival capacity of the T cell may be equally or more important to promote protection. Thus, a correlate of protection for TB vaccine development remains elusive. Future studies should address polyfunctional CD4 + T cells within the context of more comprehensive immunological signatures of protection that include other functions and phenotypes of T cells as well as the full spectrum of immune cells and mediators that participate in the immune response against Mtb.

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          Most cited references64

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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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            Disseminated tuberculosis in interferon gamma gene-disrupted mice

            The expression of protective immunity to Mycobacterium tuberculosis in mice is mediated by T lymphocytes that secrete cytokines. These molecules then mediate a variety of roles, including the activation of parasitized host macrophages, and the recruitment of other mononuclear phagocytes to the site of the infection in order to initiate granuloma formation. Among these cytokines, interferon gamma (IFN-gamma) is believed to play a key role is these events. In confirmation of this hypothesis, we show in this study that mice in which the IFN-gamma gene has been disrupted were unable to contain or control a normally sublethal dose of M. tuberculosis, delivered either intravenously or aerogenically. In such mice, a progressive and widespread tissue destruction and necrosis, associated with very high numbers of acid- fast bacilli, was observed. In contrast, despite the lack of protective immunity, some DTH-like reactivity could still be elicited. These data, therefore, indicate that although IFN-gamma may not be needed for DTH expression, it plays a pivotal and essential role in protective cellular immunity to tuberculosis infection.
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              Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice.

              Understanding the immunological mechanisms of protection and pathogenesis in tuberculosis remains problematic. We have examined the extent to which tumor necrosis factor-alpha (TNF alpha) contributes to this disease using murine models in which the action of TNF alpha is inhibited. TNF alpha was neutralized in vivo by monoclonal antibody; in addition, a mouse strain with a disruption in the gene for the 55 kDa TNF receptor was used. The data from both models established that TNF alpha and the 55 kDa TNF receptor are essential for protection against tuberculosis in mice, and for reactive nitrogen production by macrophages early in infection. Granulomas were formed in equal numbers in control and experimental mice, but necrosis was observed only in mice deficient in TNF alpha or TNF receptor. TNF alpha and the 55 kDa TNF receptor are necessary conditions for protection against murine M. tuberculosis infection, but are not solely responsible for the tissue damage observed.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/460208
                URI : http://frontiersin.org/people/u/482071
                URI : http://frontiersin.org/people/u/467649
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                05 October 2017
                2017
                : 8
                : 1262
                Affiliations
                [1] 1Division of Infectious Disease, Department of Pediatrics, Oregon Health and Science University , Portland, OR, United States
                [2] 2Pulmonary and Critical Care Medicine, Department of Medicine, Oregon Health and Science University , Portland, OR, United States
                [3] 3Department of Medicine, VA Portland Health Care System , Portland, OR, United States
                [4] 4South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM) and Division of Immunology, Department of Pathology, University of Cape Town , Cape Town, South Africa
                Author notes

                Edited by: Ulrich Emil Schaible, Forschungszentrum Borstel (LG), Germany

                Reviewed by: Juraj Ivanyi, King’s College London, United Kingdom; Camille Locht, Institut national de la santé et de la recherche médicale (INSERM), France

                *Correspondence: Deborah A. Lewinsohn, lewinsde@ 123456ohsu.edu

                Specialty section: This article was submitted to Vaccines and Molecular Therapeutics, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2017.01262
                5633696
                29051764
                54f49926-d5e9-4476-9017-4409196800a3
                Copyright © 2017 Lewinsohn, Lewinsohn and Scriba.

                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) or licensor 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 July 2017
                : 21 September 2017
                Page count
                Figures: 0, Tables: 5, Equations: 0, References: 94, Pages: 22, Words: 17833
                Funding
                Funded by: Bill and Melinda Gates Foundation 10.13039/100000865
                Categories
                Immunology
                Review

                Immunology
                t-cell immunity,cd4+ t cells,vaccine-induced immunity,tuberculosis,vaccine,protective immunity,bcg,polyfunctional t cells

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