Document Type

Journal Article

Publication Date

2017

Journal

Frontiers in Immunology

DOI

10.3389/fimmu.2017.00097

Abstract

Human T-cell lymphotropic virus (HTLV)-1 was the first human retrovirus to be associated to cancer, namely Adult T-cell Leukemia (ATL), but its pathogenesis remains enigmatic, since only a minority of infected individuals develops either ATL or the neuroinflammatory disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A functional FAS -670 polymorphism in an interferon (IFN)-regulated STAT1-binding site has been associated to both ATL and HAM/TSP susceptibility. Fashi T stem cell memory (Tscm) cells have been identified as the hierarchical apex of ATL, but have not been investigated in HAM/TSP. In addition, both FAS and STAT1 have been identified in an IFN-inducible HAM/TSP gene signature, but its pathobiological significance remains unclear. We comprehensively explored Fas expression (protein/mRNA) and function in lymphocyte activation, apoptosis, proliferation and transcriptome, in PBMC from a total of 47 HAM/TSP patients, 40 asymptomatic HTLV-1-infected individuals (AC) and 58 HTLV-1 -uninfected healthy controls.
Fas surface expression followed a two-step increase from HC to AC and from AC to HAM/TSP. In HAM/TSP, Fas levels correlated positively to lymphocyte activation markers, but negatively to age of onset, linking Fashi cells to earlier, more aggressive disease. Surprisingly, increased lymphocyte Fas expression in HAM/TSP was linked to decreased apoptosis and increased lymphoproliferation upon in vitro culture, but not to proviral load. This Fashi phenotype is HAM/TSP-specific, since both ex vivo and in vitro Fas expression was increased as compared to multiple sclerosis another neuroinflammatory disorder. To elucidate the molecular mechanism underlying non-apoptotic Fas signalling in HAM/TSP, we combined transcriptome analysis with functional assays, i.e. blocking vs. triggering Fas receptor in vitro with antagonist and agonist- anti-Fas mAb, respectively. Treatment with agonist anti-Fas mAb restored apoptosis, indicating biased but not defective Fas signalling in HAM/TSP. In silico analysis revealed biased Fas signalling towards proliferation and inflammation, driven by RelA/NF-kB. Correlation of Fas transcript levels with proliferation (but not apoptosis) was confirmed in HAM/TSP ex vivo transcriptomes. In conclusion, we demonstrated a two-step increase in Fas expression, revealing a unique Fashi lymphocyte phenotype in HAM/TSP, distinguishable from multiple sclerosis. Non-apoptotic Fas signalling might fuel HAM/TSP pathogenesis, through increased lymphoproliferation, inflammation and early age of onset.

Comments

This is a provisional PDF. The publisher's final formatted version will be available shortly.

Reproduced with permission of Frontiers Media S.A. Frontiers in Immunology

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Peer Reviewed

1

Open Access

1

Share

COinS