Clonally Expanded CD8 T Cells Are Recruited to the CSF in Neurosarcoidosis Through the Chemokine Receptors CXCR3 and CXCR4

Sarcoidosis is an idiopathic granulomatous disease that damages multiple vital organs, including the central nervous system (CNS), i.e., Neurosarcoidosis. How antigen-specific lymphocytes are recruited to the CNS in Neurosarcoidosis remains poorly defined. To identify cerebrospinal fluid (CSF) specific, antigen-driven T and B cell responses, we performed single-cell RNA sequencing of CSF and blood cells from Neurosarcoid participants coupled to T and B cell receptor sequencing. In contrast to pulmonary sarcoidosis, which is driven by CD4 T cells, we found consistent CD8 T cell clonal expansion enriched in the CSF. These CSF-enriched CD8 T cells were composed of two subsets based on chemokine expression: EBI2⁺CXCR3⁺ dual expressors and CXCR4⁺ single expressors. Correspondingly, the ligands for CXCR3 (CXCL9 & CXCL10) and CXCR4 (CXCL12) were elevated in the CSF compared to the blood. Finally, we found a specific reduction of EBI2⁺CXCR3⁺ dual expressors and CXCR4⁺ single expressors in blood CD8 T cells in Neurosarcoidosis, but not healthy controls, consistent with recruitment out of the blood into the CNS. Thus, anti-specific CD8 T cells appear to be recruited to the CNS in Neurosarcoidosis via two parallel chemokine axes.