Long-term effects of HTLV-1 on brain astrocytes: Sustained expression of Tax-1 associated with synthesis of inflammatory mediators

Szymocha, Raphae; Brisson, Christine; Bernard, Arlette; Akaoka, H.; Belin, Marie‐Françoise; Giraudon, Pascale

doi:10.3109/13550280009030761

Cited by 34 publications

(36 citation statements)

References 35 publications

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“…Interestingly, HAM/TSP patients currently display a chronic activation status and a high migratory rate of T cells associated with an enhanced secretion of chemokines and semaphorins (45, 46, 64 -66). Our data suggest that, following T cell activation at the periphery, CRMP2 could promote the chemokine-directed T cells trafficking, favoring their recruitment to inflamed CNS then participating in the T cell-mediated impairment of neural cell survival and function, as described previously (66,67). Preliminary data on the migratory rate of activated cells selected from HTLV-I-infected patients support this hypothesis.…”

Section: Discussionsupporting

confidence: 71%

A Role for the Neuronal Protein Collapsin Response Mediator Protein 2 in T Lymphocyte Polarization and Migration

Vincent

Collette

Marignier

et al. 2005

The Journal of Immunology

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The semaphorin-signaling transducer collapsin response mediator protein 2 (CRMP2) has been identified in the nervous system where it mediates Sema3A-induced growth cone navigation. In the present study, we provide first evidence that CRMP2 is present in the immune system and plays a critical role in T lymphocyte function. CRMP2 redistribution at the uropod in polarized T cells, a structural support of lymphocyte motility, suggests that it may regulate T cell migration. This was evidenced in primary T cells by small-interfering RNA-mediated CRMP2 gene silencing and blocking Ab, as well as CRMP2 overexpression in Jurkat T cells tested in a chemokine- and semaphorin-mediated transmigration assay. Expression analysis in PBMC from healthy donors showed that CRMP2 is enhanced in cell subsets bearing the activation markers CD69+ and HLA-DR+. Heightened expression in T lymphocytes of patients suffering from neuroinflammatory disease with enhanced T cell-transmigrating activity points to a role for CRMP2 in pathogenesis. The elucidation of the signals and mechanisms that control this pathway will lead to a better understanding of T cell trafficking in physiological and pathological situations.

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Section: Discussionsupporting

confidence: 71%

A Role for the Neuronal Protein Collapsin Response Mediator Protein 2 in T Lymphocyte Polarization and Migration

Vincent

Collette

Marignier

et al. 2005

The Journal of Immunology

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“…RNA was isolated with the use of RNA PLUS (Qbiogen), residual genomic DNA was removed using Dnase I (DNase-free, Ambion), and reverse transcription was performed [500 ng total treated RNA and 100 ng oligo [dT] [12][13][14][15][16][17][18] primers (33) …”

Section: Real-time Pcrmentioning

confidence: 99%

“…In fact, Tax has the ability to promote or alter the expression and activity of several cellular factors involved in T cell behavior (11)(12)(13), as such, may contribute to pathogenic mechanism. In this context, we have previously shown that HTLV-1-infected T cells disturb the metabolism of astrocytes through the activity of TNF-a (14). Secreted by infected T lymphocytes, TNF-a reduced the glutamate transporter EAAT2/GLT1 at astrocyte membrane and, consequently, increased the extracellular level of glutamate, an excitotoxic amino acid deleterious for neurons and oligodendrocytes at a high level.…”

mentioning

confidence: 99%

Human T Lymphotropic Virus Type 1 Increases T Lymphocyte Migration by Recruiting the Cytoskeleton Organizer CRMP2

Varrin‐Doyer

Nicolle

Marignier

et al. 2012

The Journal of Immunology

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Recruitment of virus-infected T lymphocytes into the CNS is an essential step in the development of virus-associated neuroinflammatory diseases, notably myelopathy induced by retrovirus human T leukemia virus-1 (HTLV-1). We have recently shown the key role of collapsin response mediator protein 2 (CRMP2), a phosphoprotein involved in cytoskeleton rearrangement, in the control of human lymphocyte migration and in brain targeting in animal models of virus-induced neuroinflammation. Using lymphocytes cloned from infected patients and chronically infected T cells, we found that HTLV-1 affects CRMP2 activity, resulting in an increased migratory potential. Elevated CRMP2 expression accompanies a higher phosphorylation level of CRMP2 and its more pronounced adhesion to tubulin and actin. CRMP2 forms, a full length and a shorter, cleaved one, are also affected. Tax transfection and extinction strategies show the involvement of this viral protein in enhanced full-length and active CRMP2, resulting in prominent migratory rate. A role for other viral proteins in CRMP2 phosphorylation is suspected. Full-length CRMP2 confers a migratory advantage possibly by preempting the negative effect of short CRMP2 we observe on T lymphocyte migration. In addition, HTLV-1–induced migration seems, in part, supported by the ability of infected cell to increase the proteosomal degradation of short CRMP2. Finally, gene expression in CD69+ cells selected from patients suggests that HTLV-1 has the capacity to influence the CRMP2/PI3K/Akt axis thus to positively control cytoskeleton organization and lymphocyte migration. Our data provide an additional clue to understanding the infiltration of HTLV-1–infected lymphocytes into various tissues and suggest that the regulation of CRMP2 activity by virus infection is a novel aspect of neuroinflammation.

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“…Previous studies have shown that human astrogliomas can be infected with HTLV-1 in vitro (55,63) and that infection correlates with the induction of the proinflammatory cytokines TNF-␣ and IL-1␣ (36,53). To systematically evaluate the role of Tax1 and Tax2 expression in neuroglial cells, a lentiviral vector system capable of cotransducing the HTLV-1 Tax and the green fluorescent protein (GFP) reporter gene was used.…”

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confidence: 99%

Proinflammatory Cytokine Gene Induction by Human T-Cell Leukemia Virus Type 1 (HTLV-1) and HTLV-2 Tax in Primary Human Glial Cells

Banerjee¹,

Rochford²,

Antel

et al. 2007

J Virol

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Infection with human T-cell leukemia virus type 1 (HTLV-1) can result in the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic inflammatory disease of the central nervous system (CNS). HTLV-2 is highly related to HTLV-1 at the genetic level and shares a high degree of sequence homology, but infection with HTLV-2 is relatively nonpathogenic compared to HTLV-1. Although the pathogenesis of HAM/TSP remains to be fully elucidated, previous evidence suggests that elevated levels of the proinflammatory cytokines in the CNS are associated with neuropathogenesis. We demonstrate that HTLV-1 infection in astrogliomas results in a robust induction of interleukin-1␤ (IL-1␤), IL-1␣, tumor necrosis factor alpha (TNF-␣), TNF-␤, and IL-6 expression. HTLV encodes for a viral transcriptional transactivator protein named Tax that also induces the transcription of cellular genes. To investigate and compare the effects of Tax1 and Tax2 expression on the dysregulation of proinflammatory cytokines, lentivirus vectors were used to transduce primary human astrocytomas and oligodendrogliomas. The expression of Tax1 in primary human astrocytomas and oligodendrogliomas resulted in significantly higher levels of proinflammatory cytokine gene expression compared to Tax2. Notably, Tax1 expression uniquely sensitized primary human astrocytomas to apoptosis. A Tax2/Tax1 chimera encoding the C-terminal 53 amino acids of the Tax1 fused to the Tax2 gene (Tax 221 ) demonstrated a phenotype that resembled Tax1, with respect to proinflammatory cytokine gene expression and sensitization to apoptosis. The patterns of differential cytokine induction and sensitization to apoptosis displayed by Tax1 and Tax2 may reflect differences relating to the heightened neuropathogenicity associated with HTLV-1 infection and the development of HAM/TSP.Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of a slow progressive neurological disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) (42). Although most HTLV-1-infected individuals remain asymptomatic carriers, an estimated 5 to 10% of HTLV-1-infected individuals develop HAM/TSP. HTLV-2 was originally isolated from a patient with an atypical hairy cell leukemia and shares ca. 70% sequence homology with HTLV-1. To date, HTLV-2 infection has been rarely and controversially linked to the development of neurodegenerative diseases (2, 30).Cytokines play a critical role in physiological processes in the central nervous system (CNS), including establishing and maintaining normal homeostasis, as well as mediating inflammatory and immune responses. Cytokines have also been implicated as being the major mediators of demyelination in the CNS, resulting in a variety of inflammatory and neoplastic diseases (1). Elevated levels of tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (IL-1␤), IL-1␣, and IL-6 have previously been detected in the cerebrospinal fluid of HAM/TSP patients (28,40,57), suggesting that increased expression of these proi...

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Long-term effects of HTLV-1 on brain astrocytes: Sustained expression of Tax-1 associated with synthesis of inflammatory mediators

Cited by 34 publications

References 35 publications

A Role for the Neuronal Protein Collapsin Response Mediator Protein 2 in T Lymphocyte Polarization and Migration

A Role for the Neuronal Protein Collapsin Response Mediator Protein 2 in T Lymphocyte Polarization and Migration

Human T Lymphotropic Virus Type 1 Increases T Lymphocyte Migration by Recruiting the Cytoskeleton Organizer CRMP2

Proinflammatory Cytokine Gene Induction by Human T-Cell Leukemia Virus Type 1 (HTLV-1) and HTLV-2 Tax in Primary Human Glial Cells

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