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CD4 T Cell-Derived IFN-γ Plays a Minimal Role in Control of Pulmonary Mycobacterium tuberculosis Infection and Must Be Actively Repressed by PD-1 to Prevent Lethal Disease

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      Abstract

      IFN-γ–producing CD4 T cells are required for protection against Mycobacterium tuberculosis (Mtb) infection, but the extent to which IFN-γ contributes to overall CD4 T cell-mediated protection remains unclear. Furthermore, it is not known if increasing IFN-γ production by CD4 T cells is desirable in Mtb infection. Here we show that IFN-γ accounts for only ~30% of CD4 T cell-dependent cumulative bacterial control in the lungs over the first six weeks of infection, but >80% of control in the spleen. Moreover, increasing the IFN-γ–producing capacity of CD4 T cells by ~2 fold exacerbates lung infection and leads to the early death of the host, despite enhancing control in the spleen. In addition, we show that the inhibitory receptor PD-1 facilitates host resistance to Mtb by preventing the detrimental over-production of IFN-γ by CD4 T cells. Specifically, PD-1 suppressed the parenchymal accumulation of and pathogenic IFN-γ production by the CXCR3+KLRG1-CX3CR1- subset of lung-homing CD4 T cells that otherwise mediates control of Mtb infection. Therefore, the primary role for T cell-derived IFN-γ in Mtb infection is at extra-pulmonary sites, and the host-protective subset of CD4 T cells requires negative regulation of IFN-γ production by PD-1 to prevent lethal immune-mediated pathology.

      Author Summary

      The development of novel tuberculosis vaccines has been hindered by the poor understanding of the mechanisms of host-protection. It has been long-held that IFN-γ is the principle effector of CD4 T cell-mediated resistance to Mtb infection, but Mtb-specific CD4 T cells produce low amounts of IFN-γ in vivo, leading to the possibility that increasing IFN-γ production by Th1 cells might enhance control of Mtb infection. However, the precise contribution of IFN-γ to CD4 T cell-dependent protection and the outcome of increasing IFN-γ production by CD4 T cells have not been evaluated. Here we show that IFN-γ accounts for only ~30% of the cumulative CD4 T cell-mediated reduction in lung bacterial loads over the first 1.5 months of infection. Moreover, we find that increasing the per capita production of IFN-γ by CD4 T cells leads to the early death of the host. Lastly, we show that suppression of CD4 T cell-derived IFN-γ by the inhibitory receptor PD-1 is essential to prevent lethal disease. Therefore, poor control Mtb infection does not result from defective production of IFN-γ, and strategies to selectively boost it are unwarranted. Furthermore, identifying the primary mechanisms of CD4 T cell-dependent control of Mtb infection should be a priority.

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      Most cited references 68

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      PD-1 and its ligands in tolerance and immunity.

      Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance, and immunopathology. Immune responses to foreign and self-antigens require specific and balanced responses to clear pathogens and tumors and yet maintain tolerance. Induction and maintenance of T cell tolerance requires PD-1, and its ligand PD-L1 on nonhematopoietic cells can limit effector T cell responses and protect tissues from immune-mediated tissue damage. The PD-1:PD-L pathway also has been usurped by microorganisms and tumors to attenuate antimicrobial or tumor immunity and facilitate chronic infection and tumor survival. The identification of B7-1 as an additional binding partner for PD-L1, together with the discovery of an inhibitory bidirectional interaction between PD-L1 and B7-1, reveals new ways the B7:CD28 family regulates T cell activation and tolerance. In this review, we discuss current understanding of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential.
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        Restoring function in exhausted CD8 T cells during chronic viral infection.

        Functional impairment of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T-cell dysfunction are not well understood. To address this question, we analysed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8 T cells. Here we report that PD-1 (programmed death 1; also known as Pdcd1) was selectively upregulated by the exhausted T cells, and that in vivo administration of antibodies that blocked the interaction of this inhibitory receptor with its ligand, PD-L1 (also known as B7-H1), enhanced T-cell responses. Notably, we found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the 'helpless' CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load. Blockade of the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory pathway had no effect on either T-cell function or viral control. These studies identify a specific mechanism of T-cell exhaustion and define a potentially effective immunological strategy for the treatment of chronic viral infections.
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          The immune response in tuberculosis.

          There are 9 million cases of active tuberculosis reported annually; however, an estimated one-third of the world's population is infected with Mycobacterium tuberculosis and remains asymptomatic. Of these latent individuals, only 5-10% will develop active tuberculosis disease in their lifetime. CD4(+) T cells, as well as the cytokines IL-12, IFN-γ, and TNF, are critical in the control of Mycobacterium tuberculosis infection, but the host factors that determine why some individuals are protected from infection while others go on to develop disease are unclear. Genetic factors of the host and of the pathogen itself may be associated with an increased risk of patients developing active tuberculosis. This review aims to summarize what we know about the immune response in tuberculosis, in human disease, and in a range of experimental models, all of which are essential to advancing our mechanistic knowledge base of the host-pathogen interactions that influence disease outcome.
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            Author and article information

            Affiliations
            [1 ]T lymphocyte Biology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
            [2 ]Department of Microbiology and Immunobiology, and Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
            [3 ]Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland, United States of America
            [4 ]Department of Microbiology, University of Tennessee, Knoxville, Tennessee, United States of America
            Harvard School of Public Health, UNITED STATES
            Author notes

            I have read the journal's policy and the authors of this manuscript have the following competing interests: DLB and AHS have patents related to PD-1. This does not alter our adherence to all PLOS Pathogens policies on sharing data and materials.

            Conceived and designed the experiments: SS DLB VVG. Performed the experiments: SS KDK MAS. Analyzed the data: SS DLB VVG. Contributed reagents/materials/analysis tools: AHS HAY. Wrote the paper: SS DLB VVG.

            Contributors
            Role: Editor
            Journal
            PLoS Pathog
            PLoS Pathog
            plos
            plospath
            PLoS Pathogens
            Public Library of Science (San Francisco, CA USA )
            1553-7366
            1553-7374
            31 May 2016
            May 2016
            : 12
            : 5
            27244558
            4887085
            10.1371/journal.ppat.1005667
            PPATHOGENS-D-16-00690
            (Editor)

            This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

            Counts
            Figures: 6, Tables: 0, Pages: 22
            Product
            Funding
            Funded by: funder-id http://dx.doi.org/10.13039/100006492, Division of Intramural Research, National Institute of Allergy and Infectious Diseases;
            Award Recipient :
            Funded by: the Kyoto University Foundation fellowship
            Award Recipient :
            Funded by: the NIH-JSPS intramural fellowship
            Award Recipient :
            Funded by: the American Heart Foundation grant
            Award Recipient :
            This work was supported by the Intramural Research Program of NIAID, NIH awarded to DLB, the American Heart Foundation grant to VVG, the Kyoto University Foundation fellowship and the NIH-JSPS intramural fellowship to SS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Categories
            Research Article
            Biology and Life Sciences
            Cell Biology
            Cellular Types
            Animal Cells
            Blood Cells
            White Blood Cells
            T Helper Cells
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            Cell Biology
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            Infectious disease & Microbiology

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