Astrocytic Fas ligand expression is required to induce T-cell apoptosis and recovery from experimental autoimmune encephalomyelitis

Authors


  • Current address: Dr. Fahad Haroon, Department of Clinical Research, Hamdard University, New Delhi, India.

Full correspondence Prof. Dirk Schlüter, Institute of Medical Microbiology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany

Fax: +49-(0)391 67290717

e-mail: dirk.schlueter@med.ovgu.de

Abstract

In T-cell-mediated autoimmune diseases of the CNS, apoptosis of Fas+ T cells by FasL contributes to resolution of disease. However, the apoptosis-inducing cell population still remains to be identified. To address the role of astrocytic FasL in the regulation of T-cell apoptosis in experimental autoimmune encephalomyelitis, we immunized C57BL/6 glial fibrillary acid protein (GFAP)-Cre FasLfl/fl mice selectively lacking FasL in astrocytes with MOG35–55 peptide. GFAP-Cre FasLfl/fl mice were unable to resolve EAE and suffered from persisting demyelination and paralysis, while FasLfl/fl control mice recovered. In contrast to FasLfl/fl mice, GFAP-Cre FasLfl/fl mice failed to induce apoptosis of Fas+ activated CD4+ T cells and to increase numbers of Foxp3+ Treg cells beyond day 15 post immunization, the time point of maximal clinical disease in control mice. The persistence of activated and GM-CSF-producing CD4+ T cells in GFAP-Cre FasLfl/fl mice also resulted in an increased IL-17, IFN-γ, TNF, and GM-CSF mRNA expression in the CNS. In vitro, FasL+ but not FasL astrocytes induced caspase-3 expression and apoptosis of activated T cells. In conclusion, FasL expression of astrocytes plays an important role in the control and elimination of autoimmune T cells from the CNS, thereby determining recovery from EAE.

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