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      High Expression of CD244 and SAP Regulated CD8+ T Cell Responses of Patients with HTLV-I Associated Neurologic Disease

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      PLoS Pathogens

      Public Library of Science

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          HTLV-I-specific CD8 + T cells have been characterized with high frequencies in peripheral blood and cerebrospinal fluid and production of proinflammatory cytokines, which contribute to central nervous system inflammation in HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, little is known about the differences in CD8 + T cell activation status between asymptomatic carrier (ACs) and patients with HAM/TSP. The expression of CD244, a signaling lymphocyte activation molecule (SLAM) family receptor, was significantly higher on CD8 + T cells in HTLV-I-infected patients, both ACs and patients with HAM/TSP, than those on healthy normal donors (NDs). Blockade of CD244 inhibited degranulation and IFN-γ production in CD8 + T cells of patients with HAM/TSP, suggesting that CD244 is associated with effector functions of CD8 + T cells in patients with HAM/TSP. Moreover, SLAM-associated protein (SAP) was overexpressed in patients with HAM/TSP compared to ACs and NDs. SAP expression in Tax-specific CTLs was correlated in the HTLV-I proviral DNA loads and the frequency of the cells in HTLV-I-infected patients. SAP knockdown by siRNA also inhibited IFN-γ production in CD8 + T cells of patients with HAM/TSP. Thus, the CD244/SAP pathway was involved in the active regulation of CD8 + T cells of patients with HAM/TSP, and may play roles in promoting inflammatory neurological disease.

          Author Summary

          Human T-lymphotropic virus type I (HTLV-I) is a retrovirus that persistently infects 20 million people worldwide. The majority of infected individuals are asymptomatic carriers of the virus, but 5–10% of infected people develop either adult T cell leukemia/lymphoma (ATL) or a chronic, progressive neurological disease termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is characterized by central nervous system (CNS) inflammation including HTLV-I-specific CD8 + T cells where disease progression and pathogenesis is associated with a dysregulation of antigen-specific CD8 + T cells, although the mechanism of this dysregulation remains to be defined. Here we demonstrate that a signaling lymphocyte activation molecule (SLAM) family of receptors, CD244, was overexpressed on CD8 + T cells of HTLV-I-infected patients than those of healthy normal donors, and that the upregulation of the adaptor protein, SAP, in CD8 + T cells distinguished HTLV-I infected individuals with and without neurologic disease. Both CD244 and SAP were associated with effector functions (high expression of IFN-γ) of CD8 + T cells in patients with HAM/TSP. This finding has important implication for T cell-mediated pathogenesis in human chronic viral infection associated with imbalance of immune function.

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          Most cited references 73

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          The specialized junction between a T lymphocyte and an antigen-presenting cell, the immunological synapse, consists of a central cluster of T cell receptors surrounded by a ring of adhesion molecules. Immunological synapse formation is now shown to be an active and dynamic mechanism that allows T cells to distinguish potential antigenic ligands. Initially, T cell receptor ligands were engaged in an outermost ring of the nascent synapse. Transport of these complexes into the central cluster was dependent on T cell receptor-ligand interaction kinetics. Finally, formation of a stable central cluster at the heart of the synapse was a determinative event for T cell proliferation.
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            T cell exhaustion often occurs during chronic infections and prevents optimal viral control. The molecular pathways involved in T cell exhaustion, however, remain poorly understood. We demonstrate that exhausted CD8+ T cells are subject to complex layers of negative regulation due to co-expression of multiple inhibitory receptors. Exhausted CD8+ T cells expressed up to 7 inhibitory receptors. Co-expression of multiple distinct inhibitory receptors correlated with greater T cell exhaustion and more severe infection. Regulation of T cell exhaustion by diverse inhibitory pathways was non-redundant since blockade of PD-1 and LAG-3 simultaneously in vivo synergistically improved T cell responses and reduced viral load. Thus, CD8+ T cell responses during chronic viral infections are regulated by complex patterns of co-expressed inhibitory receptors.
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              Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma.

              Retrovirus particles with type C morphology were found in two T-cell lymphoblastoid cell lines, HUT 102 and CTCL-3, and in fresh peripheral blood lymphocytes obtained from a patient with a cutaneous T-cell lymphoma (mycosis fungoides). The cell lines continuously produce these viruses, which are collectively referred to as HTLV, strain CR(HTLV(CR)). Originally, the production of virus from HUT 102 cells required induction with 5-iodo-2'-deoxyuridine, but the cell line became a constitutive producer of virus at its 56th passage. Cell line CTCL-3 has been a constitutive producer of virus from its second passage in culture. Both mature and immature extracellular virus particles were seen in thin-section electron micrographs of fixed, pelleted cellular material; on occasion, typical type C budding virus particles were seen. No form of intracellular virus particle has been seen. Mature particles were 100-110 nm in diameter, consisted of an electron-dense core surrounded by an outer membrane separated by an electron-lucent region, banded at a density of 1.16 g/ml on a continuous 25-65% sucrose gradient, and contained 70S RNA and a DNA polymerase activity typical of viral reverse transcriptase (RT; RNA-dependent DNA nucleotidyltransferase). Under certain conditions of assay, HTLV(CR) RT showed cation preference for Mg(2+) over Mn(2+), distinct from the characteristics of cellular DNA polymerases purified from human lymphocytes and the RT from most type C viruses. Antibodies to cellular DNA polymerase gamma and anti-bodies against RT purified from several animal retroviruses failed to detectably interact with HTLV(CR) RT under conditions that were positive for the respective homologous DNA polymerase, demonstrating a lack of close relationship of HTLV(CR) RT to cellular DNA polymerases gamma or RT of these viruses. Six major proteins, with sizes of approximately 10,000, 13,000, 19,000, 24,000, 42,000, and 52,000 daltons, were apparent when doubly banded, disrupted HTLV(CR) particles were chromatographed on a NaDodSO(4)/polyacrylamide gel. The number of these particle-associated proteins is consistent with the expected proteins of a retrovirus, but the sizes of some are distinct from those of most known retroviruses of the primate subgroups.

                Author and article information

                Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America
                Imperial College London, United Kingdom
                Author notes

                Conceived and designed the experiments: YEA SJ. Performed the experiments: YEA EM. Analyzed the data: YEA EM. Contributed reagents/materials/analysis tools: UO. Wrote the paper: YEA EM UO SJ. Performed most of the experimental work and contributed to paper writing: YEA. Analyzed immunofluorescent images and contributed to discussion and paper writing: EM. Coordinated clinical work and contributed to discussion and paper writing: UO. Supervised the project and contributed to discussion and writing: SJ.

                Role: Editor
                PLoS Pathog
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                December 2009
                December 2009
                4 December 2009
                : 5
                : 12
                This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                Pages: 12
                Research Article
                Immunology/Immunity to Infections
                Immunology/Leukocyte Activation
                Infectious Diseases/Infectious Diseases of the Nervous System
                Infectious Diseases/Viral Infections

                Infectious disease & Microbiology


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