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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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      Abstract

      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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          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.
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            Author and article information

            Affiliations
            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.

            Contributors
            Role: Editor
            Journal
            PLoS Pathog
            plos
            plospath
            PLoS Pathogens
            Public Library of Science (San Francisco, USA )
            1553-7366
            1553-7374
            December 2009
            December 2009
            4 December 2009
            : 5
            : 12
            2779586
            19997502
            09-PLPA-RA-0648R3
            10.1371/journal.ppat.1000682
            (Editor)
            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.
            Counts
            Pages: 12
            Categories
            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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