HAM/TSP-derived HTLV-1-infected T cell lines promote morphological and functional changes in human astrocytes cell lines: possible role in the enhanced T cells recruitment into Central Nervous System.

Eduardo Samo Gudo,Wilson Savino,Suse Dayse Silva-Barbosa,Leandra Linhares-Lacerda,Dumith Chequer Bou-Habib,Marcelo Ribeiro-Alves,Suzana Corte Real

doi:10.1186/s12985-015-0398-x

Abstract

BackgroundThe mechanisms through which HTLV-1 leads to and maintains damage in the central nervous system of patients undergoing HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) are still poorly understood. In recent years, increasing evidence indicates that, not only lymphocytes but also glial cells, in particular astrocytes, play a role in the pathophysiology of HAM/TSP. In this study we used a model of co-culture between human HTLV-1-infected (CIB and C91PL) and non-infected (CEM) T lymphocyte cell lines and astrocyte (U251 and U87) cell lines to mimic the in vivo T cell-astrocyte interactions.ResultsWe first observed that CIB and C91PL adhere strongly to cultured astrocytes cell lines, and that co-cultures of HTLV-1 infected and astrocyte cell lines cells resulted in rapid syncytium formation, accompanied by severe morphological alterations and increased apoptotic cell death of astrocyte cells. Additionally, cultures of astrocyte cell lines in presence of supernatants harvested from HTLV-1-infected T cell cultures resulted in significant increase in the mRNA of CCL2, CXCL1, CXCL2, CXCL3, CXCL10, IL-13, IL-8, NFKB1, TLR4, TNF, MMP8 and VCAM1, as compared with the values obtained when we applied supernatants of non-infected T- cell lines. Lastly, soluble factors secreted by cultured astrocytic cell lines primed through 1-h interaction with infected T cell lines, further enhanced migratory responses, as compared to the effect seen when supernatants from astrocytic cell lines were primed with non-infected T cell lines.ConclusionCollectively, our results show that HTLV-1 infected T lymphocyte cell lines interact strongly with astrocyte cell lines, leading to astrocyte damage and increased secretion of attracting cytokines, which in turn may participate in the further attraction of HTLV-1-infected T cells into central nervous system (CNS), thus amplifying and prolonging the immune damage of CNS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-015-0398-x) contains supplementary material, which is available to authorized users.

Highlights

The mechanisms through which Human T-cell leukemia virus type 1 (HTLV-1) leads to and maintains damage in the central nervous system of patients undergoing HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) are still poorly understood
Increased adhesion of HTLV-1-infected T lymphocyte cell lines onto astrocytoma cell lines In the first set of experiments, we investigated the adhesion of HTLV-1-infected (CIB and C91PL) and noninfected (CEM) T cell lines to astrocytoma monolayers (U251)
We found that after 30 min in cocultures, the adhesion degree of HTLV-1 infected T cell lines, (CIB in the Fig. 1b and C91PL in the Fig. 1c) to the astrocytoma cell lines was significantly higher than that of uninfected T cell lines, as illustrated by the measurement of adhesion index of CIB cells (Fig. 1d)

Summary

Introduction

The mechanisms through which HTLV-1 leads to and maintains damage in the central nervous system of patients undergoing HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) are still poorly understood. Histopathological findings of CNS revealed that HAM/ TSP affects mostly the lower and middle thoracic spinal cord, with marked degeneration of the corticospinal tracts and demyelination, accompanied by diffuse and symmetrical degeneration of the anterolateral and inner portion of the posterior columns [9]. These findings are consistent with the HAM/TSP patient’s neurological symptoms, including spastic paraplegia of the lower extremities, loss of bladder control, and sexual dysfunction [1, 10,11,12]. In vitro studies demonstrated that interactions with HTLV-1-infected lymphocytes resulted in morphological changes of astrocytes to those found in post mortem [31, 32], being accompanied by metabolic deregulation [33, 34]

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Conclusion