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Non-apoptotic Fas (CD95) Signaling on T Cells Regulates the Resolution of Th2-Mediated Inflammation.

ABSTRACT: Fas (CD95/APO-1) and its ligand (FasL/CD95L) promote the resolution of type 2 lung inflammation and eosinophilia. We previously found that Fas-deficiency on T cells, but not eosinophils, delayed resolution of inflammation. However, Fas can signal both cell death and have a positive signaling function that can actually activate cells. In this study, we investigated whether Fas-induced death or Fas-activated signaling pathways promote resolution of allergic lung inflammation. By increasing T cell survival through two Fas-independent pathways, using Bim-deficient T cells or Bcl-x_L overexpressing T cells, no differences in resolution of Th2-mediated inflammation was observed. Furthermore, Th2 cells were inherently resistant to Fas-mediated apoptosis and preferentially signaled through non-apoptotic pathways following FasL treatment. Utilizing Fas-mutant mice deficient in apoptotic but sufficient for non-apoptotic Fas signaling pathways, we demonstrate that non-apoptotic Fas signaling in T cells drives resolution of Th2-mediated airway inflammation. Our findings reveal a previously unknown role for non-apoptotic Fas signaling on Th2 cells in the induction of resolution of type 2 inflammation.

SUBMITTER: Williams JW

PROVIDER: S-EPMC6221963 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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 (MS), another neuroinflammatory disorder. To elucidate the molecular mechanism underlying non-apoptotic Fas signaling 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 signaling in HAM/TSP. In silico analysis revealed biased Fas signaling toward proliferation and inflammation, driven by RelA/NF-?B. 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 MS. Non-apoptotic Fas signaling might fuel HAM/TSP pathogenesis, through increased lymphoproliferation, inflammation, and early age of onset.

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Non-apoptotic Fas (CD95) Signaling on T Cells Regulates the Resolution of Th2-Mediated Inflammation.

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