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      Simultaneous Inhibition of T Helper 2 and T Regulatory Cell Differentiation by Small Molecules Enhances Bacillus Calmette-Guerin Vaccine Efficacy against Tuberculosis*

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          Abstract

          Background: Immunological parameters induced by BCG and the requirement of immunologic responses for optimal vaccine efficacy is incompletely understood.

          Results: Small-molecule inhibitors of Th2 and Treg cells promote BCG vaccine efficacy.

          Conclusion: Immunomodulators enhance the capacity of the BCG vaccine to protect against tuberculosis.

          Significance: Our studies reveal a simple and cost-effective approach to improve BCG vaccine efficacy.

          Abstract

          Tuberculosis affects nine million individuals and kills almost two million people every year. The only vaccine available, Bacillus Calmette-Guerin (BCG), has been used since its inception in 1921. Although BCG induces host-protective T helper 1 (Th1) cell immune responses, which play a central role in host protection, its efficacy is unsatisfactory, suggesting that additional methods to enhance protective immune responses are needed. Recently we have shown that simultaneous inhibition of Th2 cells and Tregs by using the pharmacological inhibitors suplatast tosylate and D4476, respectively, dramatically enhances Mycobacterium tuberculosis clearance and induces superior Th1 responses. Here we show that treatment with these two drugs during BCG vaccination dramatically improves vaccine efficacy. Furthermore, we demonstrate that these drugs induce a shift in the development of T cell memory, favoring central memory T (Tcm) cell responses over effector memory T (Tem) cell responses. Collectively, our findings provide evidence that simultaneous inhibition of Th2 cells and Tregs during BCG vaccination promotes vaccine efficacy.

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          Most cited references 37

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          Central memory and effector memory T cell subsets: function, generation, and maintenance.

          The memory T cell pool functions as a dynamic repository of antigen-experienced T lymphocytes that accumulate over the lifetime of the individual. Recent studies indicate that memory T lymphocytes contain distinct populations of central memory (TCM) and effector memory (TEM) cells characterized by distinct homing capacity and effector function. This review addresses the heterogeneity of TCM and TEM, their differentiation stages, and the current models for their generation and maintenance in humans and mice.
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            An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection

            Tuberculosis, a major health problem in developing countries, has reemerged in recent years in many industrialized countries. The increased susceptibility of immunocompromised individuals to tuberculosis, and many experimental studies indicate that T cell- mediated immunity plays an important role in resistance. The lymphokine interferon gamma (IFN-gamma) is thought to be a principal mediator of macrophage activation and resistance to intracellular pathogens. Mice have been developed which fail to produce IFN-gamma (gko), because of a targeted disruption of the gene for IFN-gamma. Upon infection with Mycobacterium tuberculosis, although they develop granulomas, gko mice fail to produce reactive nitrogen intermediates and are unable to restrict the growth of the bacilli. In contrast to control mice, gko mice exhibit heightened tissue necrosis and succumb to a rapid and fatal course of tuberculosis that could be delayed, but not prevented, by treatment with exogenous recombinant IFN-gamma.
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              IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge.

              Interferon-gamma is key in limiting Mycobacterium tuberculosis infection. Here we show that vaccination triggered an accelerated interferon-gamma response by CD4(+) T cells in the lung during subsequent M. tuberculosis infection. Interleukin 23 (IL-23) was essential for the accelerated response, for early cessation of bacterial growth and for establishment of an IL-17-producing CD4(+) T cell population in the lung. The recall response of the IL-17-producing CD4(+) T cell population occurred concurrently with expression of the chemokines CXCL9, CXCL10 and CXCL11. Depletion of IL-17 during challenge reduced the chemokine expression and accumulation of CD4(+) T cells producing interferon-gamma in the lung. We propose that vaccination induces IL-17-producing CD4(+) T cells that populate the lung and, after challenge, trigger the production of chemokines that recruit CD4(+) T cells producing interferon-gamma, which ultimately restrict bacterial growth.
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                Author and article information

                Journal
                J Biol Chem
                J. Biol. Chem
                jbc
                jbc
                JBC
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology (9650 Rockville Pike, Bethesda, MD 20814, U.S.A. )
                0021-9258
                1083-351X
                28 November 2014
                14 October 2014
                14 October 2014
                : 289
                : 48
                : 33404-33411
                Affiliations
                From the []Laboratory Medicine and Medical Sciences, College of Health Sciences, University of Kwazulu Natal, Durban 4001, South Africa,
                [§ ]Yogi Vemana University, Kadapa 516003, India,
                []Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, and
                []Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India
                Author notes
                [2 ] To whom correspondence should be addressed: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India and Laboratory Medicine and Medical Sciences, College of Health Sciences, UKZN, Durban 4001, South Africa. E-mail: gobardhan.das07@ 123456gmail.com .
                [1]

                Both authors contributed equally to this manuscript.

                Article
                M114.600452
                10.1074/jbc.M114.600452
                4246096
                25315774
                © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

                Author's Choice—Final version full access.

                Creative Commons Attribution Unported License applies to Author Choice Articles

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                Categories
                Immunology

                Biochemistry

                cytokine, immunotherapy, mycobacterium tuberculosis, t helper cells, vaccine

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