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      The Equivocal Role of Th17 Cells and Neutrophils on Immunopathogenesis of Leishmaniasis

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          Abstract

          Advances in the understanding of leishmaniasis progression indicate that cellular interactions more complex than the Th1/Th2 paradigm define the course of infection. Th17 cells are a crucial modulator of adaptive immunity against Leishmania parasites acting mainly on neutrophil recruitment and playing a dual role at the site of infection. This review describes the roles of both these cell types in linking innate defense responses to the establishment of specific immunity. We focus on the Th17–neutrophil interaction as a crucial component of anti- Leishmania immunity, and the clinical evolution of cutaneous or visceral leishmaniasis. To date, information obtained through experimental models and patient evaluations suggests that the influence of the presence of interleukin (IL)-17 (the main cytokine produced by Th17 cells) and neutrophils during Leishmania infections is strictly dependent on the tissue (skin or liver/spleen) and parasite species. Also, the time at which neutrophils are recruited, and the persistence of IL-17 in the infection microenvironment, may also be significant. A clearer understanding of these interactions will enable better measurement of the influence of IL-17 and its regulators, and contribute to the identification of disease/resistance biomarkers.

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          Most cited references83

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          Generation of Pathogenic Th17 Cells in the Absence of TGF-β Signaling

          CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity 1–4 . Crucial for T helper17 (Th17) cells in vivo 5,6 , IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been argued to be the factors responsible for initiating specification 7–10 . Herein, we show that Th17 differentiation can occur in the absence of TGF-β signaling. Neither IL-6 nor IL-23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naïve precursors, independently of TGF-β. Epigenetic modification of the Il17a/Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed Rorγt and T-bet. T-bet+ Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data suggest an alternative mode for Th17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore have may have therapeutic implications.
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            The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo.

            Interleukin 23 (IL-23) is required for autoimmune inflammation mediated by IL-17-producing helper T cells (T(H)-17 cells) and has been linked to many human immune disorders. Here we restricted deficiency in the IL-23 receptor to defined cell populations in vivo to investigate the requirement for IL-23 signaling in the development and function of T(H)-17 cells in autoimmunity, inflammation and infection. In the absence of IL-23, T(H)-17 development was stalled at the early activation stage. T(H)-17 cells failed to downregulate IL-2 and also failed to maintain IL-17 production or upregulate expression of the IL-7 receptor alpha-chain. These defects were associated with less proliferation; consequently, fewer effector T(H)-17 cells were produced in the lymph nodes and hence available to emigrate to the bloodstream and tissues.
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              Immunological decision-making: how does the immune system decide to mount a helper T-cell response?

              Aberrant T-cell responses underpin a range of diseases, including asthma and allergy and autoimmune diseases. Pivotal immune elements of these diseases are the development of antigen-specific effector T-helper type 2 (Th2) cells, Th1 cells, or the recently defined Th17 cells that are associated with the clinical features and disease progression. In order to identify crucial processes in the pathogenesis of these diseases it is critical to understand how the development of these T cells occurs. The phenotype of a polarized T-cell that differentiates from a naïve precursor is determined by the complex interaction of antigen-presenting cells with naïve T cells and involves a multitude of factors, including the dominant cytokine environment, costimulatory molecules, type and load of antigen presented and a plethora of signaling cascades. The decision to take the immune response in a certain direction is not made by one signal alone, instead many different elements act synergistically, antagonistically and through positive feedback loops to activate a Th1, Th2, or Th17 immune response. The elucidation of the mechanisms of selection of T-cell phenotype will facilitate the development of therapeutic strategies to intervene in the development of deleterious T-cell responses. This review will focus on the pathways and key factors responsible for the differentiation of the various subsets of effector CD4 T cells. We will primarily discuss what is known of the Th1 and Th2 differentiation pathways, while also reviewing the emerging research on Th17 differentiation.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/456557
                URI : http://frontiersin.org/people/u/489588
                URI : http://frontiersin.org/people/u/489580
                URI : http://frontiersin.org/people/u/489589
                URI : http://frontiersin.org/people/u/127108
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                30 October 2017
                2017
                : 8
                : 1437
                Affiliations
                [1] 1Department of Microbiology, Aggeu Magalhães Research Center, Oswaldo Cruz Foundation , Recife, Pernambuco, Brazil
                Author notes

                Edited by: Heinrich Korner, University of Tasmania, Australia

                Reviewed by: Hira Nakhasi, Center for Biologics Evaluation and Research (FDA), United States; Julia Walochnik, Medical University of Vienna, Austria

                *Correspondence: Milena de Paiva-Cavalcanti, mp@ 123456cpqam.fiocruz.br ; Suênia da C. Gonçalves-de-Albuquerque, sueniaaa@ 123456hotmail.com

                Specialty section: This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2017.01437
                5670345
                29163510
                a5d3daa5-1b39-4ad2-a399-e16dfa07ba68
                Copyright © 2017 Gonçalves-de-Albuquerque, Pessoa-e-Silva, Trajano-Silva, de Goes, de Morais, da C. Oliveira, de Lorena and de Paiva-Cavalcanti.

                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
                : 03 July 2017
                : 16 October 2017
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 98, Pages: 11, Words: 9698
                Funding
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico 10.13039/501100003593
                Award ID: 441584/2014-4
                Categories
                Immunology
                Review

                Immunology
                cutaneous leishmaniasis,visceral leishmaniasis,immunity,t helper 17,interleukin-17,neutrophil,immunopathogenesis

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