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      Type I Interferons Regulate Immune Responses in Humans with Blood-Stage Plasmodium falciparum Infection

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          Summary

          The development of immunoregulatory networks is important to prevent disease. However, these same networks allow pathogens to persist and reduce vaccine efficacy. Here, we identify type I interferons (IFNs) as important regulators in developing anti-parasitic immunity in healthy volunteers infected for the first time with Plasmodium falciparum. Type I IFNs suppressed innate immune cell function and parasitic-specific CD4 + T cell IFNγ production, and they promoted the development of parasitic-specific IL-10-producing Th1 (Tr1) cells. Type I IFN-dependent, parasite-specific IL-10 production was also observed in P. falciparum malaria patients in the field following chemoprophylaxis. Parasite-induced IL-10 suppressed inflammatory cytokine production, and IL-10 levels after drug treatment were positively associated with parasite burdens before anti-parasitic drug administration. These findings have important implications for understanding the development of host immune responses following blood-stage P. falciparum infection, and they identify type I IFNs and related signaling pathways as potential targets for therapies or vaccine efficacy improvement.

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          Most cited references 62

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          TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.

          We describe de novo generation of IL-17-producing T cells from naive CD4 T cells, induced in cocultures of naive CD4 T cells and naturally occurring CD4+ CD25+ T cells (Treg) in the presence of TLR3, TLR4, or TLR9 stimuli. Treg can be substituted by TGFbeta1, which, together with the proinflammatory cytokine IL-6, supports the differentiation of IL-17-producing T cells, a process that is amplified by IL-1beta and TNFalpha. We could not detect a role for IL-23 in the differentiation of IL-17-producing T cells but confirmed its importance for their survival and expansion. Transcription factors GATA-3 and T-bet, as well as its target Hlx, are absent in IL-17-producing T cells, and they do not express the negative regulator for TGFbeta signaling, Smad7. Our data indicate that, in the presence of IL-6, TGFbeta1 subverts Th1 and Th2 differentiation for the generation of IL-17-producing T cells.
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            Natural regulatory T cells in infectious disease.

            This review discusses the control exerted by natural CD4(+) CD25(+) regulatory T cells (natural T(reg) cells) during infectious processes. Natural T(reg) cells may limit the magnitude of effector responses, which may result in failure to adequately control infection. However, natural T(reg) cells also help limit collateral tissue damage caused by vigorous antimicrobial immune responses. We describe here various situations in which the balance between natural T(reg) cells and effector immune functions influences the outcome of infection and discuss how manipulating this equilibrium might be exploited therapeutically.
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              The plasticity and stability of regulatory T cells.

              Regulatory T (TReg) cells are crucial for the prevention of fatal autoimmunity in mice and humans. Forkhead box P3 (FOXP3)(+) TReg cells are produced in the thymus and are also generated from conventional CD4(+) T cells in peripheral sites. It has been suggested that FOXP3(+) TReg cells might become unstable under certain inflammatory conditions and might adopt a phenotype that is more characteristic of effector CD4(+) T cells. These suggestions have caused considerable debate in the field and have important implications for the therapeutic use of TReg cells. In this article, Nature Reviews Immunology asks several experts for their views on the plasticity and stability of TReg cells.
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                Author and article information

                Journal
                101573691
                39703
                Cell Rep
                Cell Rep
                Cell reports
                2211-1247
                24 October 2016
                4 October 2016
                27 October 2016
                : 17
                : 2
                : 399-412
                Affiliations
                [1 ]QIMR Berghofer Medical Research Institute, Royal Brisbane and Women’s Hospital, Brisbane, QLD 4006, Australia
                [2 ]School of Medicine, University of Queensland, Brisbane, QLD 4072, Australia
                [3 ]Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India
                [4 ]Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059, Australia
                [5 ]Institute of Glycomics, Griffith University, Gold Coast, Southport, QLD 4215, Australia
                [6 ]School of Natural Sciences, Griffith University, Nathan, QLD 4111, Australia
                [7 ]Menzies School of Health Research, Darwin, NT 0811, Australia
                [8 ]Charles Darwin University, Darwin, NT 0810, Australia
                [9 ]Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7BN, UK
                Author notes
                [* ]Correspondence: j.mccarthy@ 123456uq.edu.au (J.S.M.), chrise@ 123456qimr.edu.au (C.R.E.)
                [10]

                Present address: National Centre for Immunisation Research and Surveillance, Westmead, NSW 2145, Australia

                [11]

                Present address: Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4878, Australia

                [12]

                Lead Contact

                Article
                EMS70303
                10.1016/j.celrep.2016.09.015
                5082731
                27705789

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Cell biology

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