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

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 FasL(fl/fl) mice selectively lacking FasL in astrocytes with MOG(35-55) peptide. GFAP-Cre FasL(fl/fl) mice were unable to resolve EAE and suffered from persisting demyelination and paralysis, while FasL(fl/fl) control mice recovered. In contrast to FasL(fl/fl) mice, GFAP-Cre FasL(fl/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 FasL(fl/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.