Beschreibung:
<jats:p>CLN diseases are mostly fatal lysosomal storage diseases that lead to neurodegeneration in the CNS. We have previously shown that CD8+ T‐lymphocytes contribute to axonal perturbation and neuron loss in the CNS of <jats:italic>Ppt1<jats:sup>−/−</jats:sup></jats:italic> mice, a model of CLN1 disease. We now investigated the role of the inflammation‐related cell adhesion molecule sialoadhesin (Sn) in <jats:italic>Ppt1<jats:sup>−/−</jats:sup></jats:italic> and <jats:italic>Cln3<jats:sup>−/−</jats:sup></jats:italic> mice, a model of the most frequent form, CLN3 disease. Microglia/macrophages in the CNS of both models showed an upregulation of Sn and markers for proinflammatory M1 polarization and antigen presentation. Sn+ microglia/macrophages associated with SMI32+ axonal spheroids and CD8+ T‐lymphocytes. To analyze their pathogenic impact, we crossbred both models with <jats:italic>Sn</jats:italic>‐deficient mice and scored axonal degeneration and neuronal integrity using immunohistochemistry, electron microscopy and optical coherence tomography. Degenerative alterations in the retinotectal pathway of <jats:italic>Ppt1<jats:sup>−/−</jats:sup>Sn<jats:sup>−/−</jats:sup></jats:italic> and <jats:italic>Cln3<jats:sup>−/−</jats:sup>Sn<jats:sup>−/−</jats:sup></jats:italic> mice were significantly reduced. <jats:italic>Ppt1<jats:sup>−/−</jats:sup>Sn<jats:sup>−/−</jats:sup></jats:italic> mice also showed a substantially improved clinical phenotype and extended lifespan, attenuated numbers of M1‐polarized microglia/macrophages and reduced expression levels of proinflammatory cytokines. This was accompanied by an increased frequency of CD8+CD122+ T‐lymphocytes in the CNS of <jats:italic>Ppt1<jats:sup>−/−</jats:sup>Sn<jats:sup>−/−</jats:sup></jats:italic> mice, the regulatory phenotype of which was demonstrated by impaired survival of CD8+CD122− effector T‐lymphocytes in co‐culture experiments. We show for the first time that increased Sn expression on microglia/macrophages contributes to neural perturbation in two distinct models of CLN disease. Our data also indicate that a rarely described CD8+CD122+ T‐cell population can regulate the corresponding diseases. These studies provide insights into CLN pathogenesis and may guide in designing immuno‐regulatory treatment strategies. GLIA 2016;64:792–809</jats:p>