A neuronal protein fine-tunes T cell immunity in the central nervous system 2310305

Abstract

Abstract Introduction CNS autoimmune diseases such as multiple sclerosis and uveitis are driven by IL-17—producing Th17 cells, whose pathogenic conversion is promoted by IL-23 through the induction of T-bet and its downstream target IFN-γ. However, the CNS-specific signals that contribute to the pathogenic reprogramming of Th17 cells remain poorly understood. Methods We generated a dual fluorescent reporter mouse that marks the Th17 lineage and IFN-γ production to perform single-cell transcriptomic profiling of ocular T cells in experimental autoimmune uveitis (EAU). We used flow cytometry to validate candidate regulators in CNS and peripheral tissues in both wild-type and CRISPR—Cas9-engineered mice targeting genes enriched in pathogenic Th17 cells. We then evaluated disease progression in mutant mice and performed scRNA-seq analysis of ocular CD4+ T cells. We applied computational analyses to predict Th17 differentiation trajectories and disease relevance. Results Transcriptomic profiling revealed that, compared with non-pathogenic Th17 cells, pathogenic Th17 cells upregulated not only canonical inflammatory genes but also a set of neuronal genes, including neurogranin (Ng), a postsynaptic calmodulin-binding protein implicated in calcium signaling and synaptic plasticity. Using flow cytometry, we found that Ng protein is preferentially expressed by ocular Th17 cells, with minimal expression in the periphery, indicating that Ng is selectively induced in CNS-infiltrating Th17 cells. Ng-KO mice developed more severe EAU, consistent with scRNA-seq analysis of ocular CD4+ T cells showing enrichment of immune activation pathways in Ng-deficient eyes. Conclusion We propose that Ng restrains Th17 pathogenicity within the CNS, potentially by modulating TCR—driven calcium signaling. Our findings uncover an unexpected convergence of neuronal and immune programs and suggest that tissue-adapted T cells can repurpose neuronal gene networks to fine-tune local autoimmune responses in the CNS. Funding Source n/a Topic Categories Basic Autoimmunity (BA)