In agreement with Bechmann et al [21], who demonstrated that ast

In agreement with Bechmann et al. [21], who demonstrated that astrocytes induced apoptosis of activated T cells in a FasL-dependent way in vitro, we observed that FasL+ astrocytes induced apoptosis of activated Fas+ CD4+ T cells in vitro. Since astrocytes are also FasL+ in MS, our data suggest a similar role of astrocytes for the elimination of inflammatory leukocytes in this severe

human autoimmune PLX3397 nmr disease. Astrocytic FasL was protective for mice during EAE, since MOG35–55-immunized mice lacking astrocyte-specific FasL suffered from a clinically more severe EAE compared with their control littermates. The onset of clinical symptoms was similar in both GFAP-Cre FasLfl/fl and control FasLfl/fl mice at day 9 p.i. indicating that homing of myelin-specific leucocytes was not regulated by astrocytic FasL expression. In addition, the clinical score of GFAP-Cre see more FasLfl/fl and FasLfl/fl mice

increased with the same kinetics until the peak of disease in FasLfl/fl mice at day 15 p.i. In accordance, numbers of CD4+ T cells were not significantly increased in GFAP-Cre FasLfl/fl mice at day 15 p.i. However, during the clinical recovery phase of FasLfl/fl mice (day 22 p.i.), numbers of CD4+ T cells were significantly increased in the spinal cord of GFAP-Cre FasLfl/fl mice as shown by both flow cytometry and histology at day 22 p.i. The reduced number of CD4+ T cells positive for 7-AAD, which identifies late apoptotic and dead cells, illustrates the compromised ability of FasL-deficient astrocytes to induce apoptosis and elimination of infiltrating autoimmune T cells. The kinetics of disease and intraspinal CD4+ T-cell numbers indicate that FasL-dependent elimination of CD4+ T cells in EAE plays

a particularly protective role in the recovery phase. Noteworthy, the more severe EAE of GFAP-Cre FasLfl/fl mice cannot be attributed to the GFAP-Cre transgene, since C57BL/6 GFAP-Cre mice without a loxP-flanked gene develop the same course of EAE as compared to WT mice [23]. We also observed a significantly higher number of activated CD25+ CD4+ T cells and a significantly reduced Olopatadine number of Foxp3+ regulatory CD4+ T cells in the spinal cord of GFAP-Cre FasLfl/fl as compared with FasLfl/fl mice at day 22 p.i. Lack of astrocytic FasL expression altered the ratio of activated CD25+ versus regulatory Foxp3+ CD4+ T cells in the spinal cord from 5:1 in FasLfl/fl mice to 10:1 in GFAP-Cre FasLfl/fl mice. These data suggest that astrocytic FasL expression predominantly contributes to elimination of activated disease-promoting CD25+ CD4+ T cells but not of protective regulatory Foxp3+ CD4+ T cells in order to recover from EAE and to achieve a restitutio ad integrum.

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