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      Th2-polarised PrP-specific Transgenic T-cells Confer Partial Protection against Murine Scrapie

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          Several hurdles must be overcome in order to achieve efficient and safe immunotherapy against conformational neurodegenerative diseases. In prion diseases, the main difficulty is that the prion protein is tolerated as a self protein, which prevents powerful immune responses. Passive antibody therapy is effective only during early, asymptomatic disease, well before diagnosis is made. If efficient immunotherapy of prion diseases is to be achieved, it is crucial to understand precisely how immune tolerance against the prion protein can be overcome and which effector pathways may delay disease progression. To this end, we generated a transgenic mouse that expresses the ß-chain of a T cell receptor recognizing a PrP epitope presented by the class II major histocompatibility complex. The fact that the constraint is applied to only one TCR chain allows adaptation of the other chain according to the presence or absence of tolerogenic PrP. We first show that transgene-bearing T cells, pairing with rearranged α-chains conferring anti-PrP specificity, are systematically eliminated during ontogeny in PrP+ mice, suggesting that precursors with good functional avidity are rare in a normal individual. Second, we show that transgene-bearing T cells with anti-PrP specificity are not suppressed when transferred into PrP+ recipients and proliferate more extensively in a prion-infected host. Finally, such T cells provide protection through a cell-mediated pathway involving IL-4 production. These findings support the idea that cell-mediated immunity in neurodegenerative conditions may not be necessarily detrimental and may even contribute, when properly controlled, to the resolution of pathological processes.

          Author Summary

          It is generally accepted that prion-specific antibodies can protect against mouse scrapie infection. However, passive antibody therapy is limited to the lymphoinvasion stage of the disease. Active immunization has been attempted but the results have been disappointing. There is therefore a need for developing analytical models that will allow a fine dissection of the immune mechanisms at play in prion diseases and help distinguish between protective effects mediated by B cells and antibodies, and the effect of T cells. The aim of our study was to thoroughly examine T cell tolerance to the prion protein and to evaluate whether a pure specific population of T cells adoptively transferred to a normal host could proliferate and confer protection against scrapie. We designed a transgenic mouse in which the majority of T lymphocytes recognize the prion protein. Our key findings are that prion-specific T cells remain functional when transferred to normal recipients, even more so when the host is infected with scrapie, and confer partial protection against the disease by slowing down prion replication, in complete absence of anti-prion antibodies. Anti-prion T cells may therefore be considered as a therapeutic tool in the future.

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          Most cited references 55

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           S B Prusiner (1998)
          Prions are unprecedented infectious pathogens that cause a group of invariably fatal neurodegenerative diseases by an entirely novel mechanism. Prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (PrP). Bovine spongiform encephalopathy (BSE), scrapie of sheep, and Creutzfeldt-Jakob disease (CJD) of humans are among the most notable prion diseases. Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrPSc). The normal, cellular PrP (PrPC) is converted into PrPSc through a posttranslational process during which it acquires a high beta-sheet content. The species of a particular prion is encoded by the sequence of the chromosomal PrP gene of the mammals in which it last replicated. In contrast to pathogens carrying a nucleic acid genome, prions appear to encipher strain-specific properties in the tertiary structure of PrPSc. Transgenetic studies argue that PrPSc acts as a template upon which PrPC is refolded into a nascent PrPSc molecule through a process facilitated by another protein. Miniprions generated in transgenic mice expressing PrP, in which nearly half of the residues were deleted, exhibit unique biological properties and should facilitate structural studies of PrPSc. While knowledge about prions has profound implications for studies of the structural plasticity of proteins, investigations of prion diseases suggest that new strategies for the prevention and treatment of these disorders may also find application in the more common degenerative diseases.
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            Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses.

            Naturally occurring CD4+ regulatory T cells, the majority of which express CD25, are engaged in dominant control of self-reactive T cells, contributing to the maintenance of immunologic self-tolerance. Their depletion or functional alteration leads to the development of autoimmune disease in otherwise normal animals. The majority, if not all, of such CD25+CD4+ regulatory T cells are produced by the normal thymus as a functionally distinct and mature subpopulation of T cells. Their repertoire of antigen specificities is as broad as that of naive T cells, and they are capable of recognizing both self and nonself antigens, thus enabling them to control various immune responses. In addition to antigen recognition, signals through various accessory molecules and via cytokines control their activation, expansion, and survival, and tune their suppressive activity. Furthermore, the generation of CD25+CD4+ regulatory T cells in the immune system is at least in part developmentally and genetically controlled. Genetic defects that primarily affect their development or function can indeed be a primary cause of autoimmune and other inflammatory disorders in humans. Based on recent advances in our understanding of the cellular and molecular basis of this T cell-mediated immune regulation, this review discusses how naturally arising CD25+CD4+ regulatory T cells contribute to the maintenance of immunologic self-tolerance and negative control of various immune responses, and how they can be exploited to prevent and treat autoimmune disease, allergy, cancer, and chronic infection, or establish donor-specific transplantation tolerance.
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              Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein.

              PrPC is a host protein anchored to the outer surface of neurons and to a lesser extent of lymphocytes and other cells. The transmissible agent (prion) responsible for scrapie is believed to be a modified form of PrPC. Mice homozygous for disrupted PrP genes have been generated. Surprisingly, they develop and behave normally for at least seven months, and no immunological defects are apparent. It is now feasible to determine whether mice devoid of PrPC can propagate prions and are susceptible to scrapie pathogenesis.

                Author and article information

                Role: Editor
                PLoS Pathog
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                September 2011
                September 2011
                1 September 2011
                : 7
                : 9
                [1 ]UPMC Univ Paris 6, UMR_S 938, Centre de Recherche Hôpital Saint-Antoine, Paris, France
                [2 ]INSERM, UMR_S 938, Centre de Recherche Hôpital Saint-Antoine, Paris, France
                [3 ]Unité du Développement des Lymphocytes, Institut Pasteur, Paris and INSERM U668, Paris, France
                University of Edinburgh, United Kingdom
                Author notes

                ¤a: Current address: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America

                ¤b: Current address: Unité Mixte de Recherche 7211, Hôpital Pitié-Salpêtrière, Paris, France

                Conceived and designed the experiments: SI VB CC. Performed the experiments: SI VB PG AL SG TC. Analyzed the data: SI VB PG CC. Contributed reagents/materials/analysis tools: AL. Wrote the paper: VB PA CC.

                ¶ These authors contributed equally to this work and share first authorship.

                Iken et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Pages: 13
                Research Article
                Clinical Immunology
                Immune Cells
                T Cells
                Immune Response
                Infectious Diseases
                Prion Diseases

                Infectious disease & Microbiology


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