We have recently established Rnaset2-/- mice as a model system to improve the pathophysiological understanding of infantile-onset RNaseT2-deficient leukoencephalopathies and type I interferonopathies. Rnaset2-/- mice were viable and healthy at birth, but displayed upregulation of type I interferon-stimulated genes in all organs examined. At 20 weeks of age, RNaseT2-deficient animals developed IFNAR1-dependent neuroinflammation, characterized primarily by the presence of CD8 T cells and inflammatory monocytes. Single nuclei transcriptome analyses revealed homeostatic dysfunction in glial cells and neurons, while magnetic resonance imaging indicated hippocampal-accentuated brain atrophy.To investigate the role of CD8 T cells in neuroinflammation and neurodegeneration in RNaseT2-deficient mice, we crossed Rnaset2-/- mice with CD8a-deficient animals and conducted ex vivo MRI, flow cytometry, and histological analyses. Rnaset2-/- CD8a-/- mice exhibited normal T2-relaxation times on MRI, suggesting a significantly reduced neuroinflammatory response compared to CD8 competent Rnaset2-/- mice. Consistent with this, flow cytometric analysis of CNS leukocytes demonstrated a lack of CD8 T cells and reduced numbers of CD4 T cells and inflammatory monocytes infiltrating the CNS in Rnaset2-/- CD8a-/- mice. Notably, morphometric analysis of the CNS by MRI also revealed less hippocampal atrophy in Rnaset2-/- CD8a-/- mice compared to Rnaset2-/- controls.In summary, we provide evidence that CD8 T cells contribute to neuroinflammation and neurodegeneration in Rnaset2-/- animals. Leveraging RNaseT2-deficient mice could provide new mechanistic insights into how CD8 T cells might foster neurodegeneration.