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

- Sandhoff mouse model (Hexb−/−) has proven to be an excellent prototype for both Sandhoff and Tay Sachs diseases.
- Hexb−/−Il−15−/− mice are utilized to examine the role of NK and CD8+ T cells during Sandhoff disease pathogenesis.
- Increased prevalence of CD4+ T helper cells and CD8+ cytotoxic T lymphocytes in observed in brains of Sandoff mice.
- Astrogliosis was significantly reduced in the cerebellum of Hexb−/−Il−15−/− mice; however, microgliosis was not affected.
- IL-15 depletion reduces numbers of NK/CD8+ T cells and astrocytes but accelerates disease progression in Sandhoff mice.
- Expansion of NK and CD8+ T cells populations with IL-15 may have therapeutic benefits for Sandhoff disease.

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 ± 3.5 d, compared to Hexb −/− mice (127 ± 2.2 d). 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.