Suppression of NK and CD8+ T cells reduces astrogliosis but accelerates cerebellar dysfunction and shortens life span in a mouse model of Sandhoff disease

Abstract

Sandhoff disease is an inherited lysosomal storage disease, resulting from the deficiency of lysosomal β-hexosaminidase A and B enzyme activity. The Hexb−/− mouse model recapitulates human disease and leads to fatal neurodegeneration and neuroinflammation. IL-15 is important for the proliferation of NK, NK T, and CD8+ cytotoxic/memory T cells. In order to determine how changes to IL-15-dependent immune cell populations would alter the course of Sandhoff disease in mice, we generated a Hexb−/−Il-15−/− double knockout mouse and used motor behaviour tests, analyzed peripheral blood and brain leukocyte immunophenotypes, cytokine secretion, as well as examined markers of microgliosis, astrogliosis and apoptosis. Hexb−/−Il-15−/− mice had an accelerated neurodegenerative phenotype, and reached the humane endpoint at 118±3.5d, compared to Hexb−/− mice (127±2.2d). The performance of Hexb−/−Il-15−/− mice declined earlier than Hexb−/− mice on the rotarod and righting reflex motor behaviour tests. Hexb−/− mice had a significantly higher prevalence of pro-inflammatory monocytes in the blood relative to C57BL/6 mice, but this was unaltered by IL-15 deficiency. The prevalence of NK cells and CD8+ T cells in Il-15−/− and Hexb−/−Il-15−/− mice was decreased compared to wild type and Hexb−/− mice. While Hexb−/− mice displayed an increase in the prevalence of CD4+ and CD8+ T cells in brain leukocytes compared to C57BL/6 mice, there was a decrease in CD8+ T cells in Hexb−/−Il-15−/− compared to Hexb−/− mice. In addition, circulating IL-17 and IL-10 levels were significantly higher in Hexb−/−Il-15−/− mice, suggesting heightened inflammation compared to Hexb−/− mice. Interestingly, astrogliosis levels were significantly reduced in the cerebellum of Hexb−/−Il-15−/− mice compared to Hexb−/− mice while microgliosis was not affected in brains of Hexb−/−Il-15−/− mice. Our study demonstrated that IL-15 depletion dramatically reduced numbers of NK and CD8+ T cells as well as astrocytes but accelerated disease progression in Sandhoff mice. These results pointed to interactions between NK/CD8+ T cells and astrogliosis and potentially a protective role for NK/CD8+ T cells and/or astrocytes during disease progression. This observation supports the notion that expanding the IL-15-dependent NK and CD8+ T cells populations with IL-15 therapy may have therapeutic benefits for Sandhoff disease.