CLEC12A signaling represses protective immune responses and contributes to hippocampal pathology in neurotropic picornavirus infection

Neurotropic viruses infect the central nervous system (CNS) and can cause severe neurological disorders. Theiler's murine encephalomyelitis virus (TMEV) infection in C57BL/6 mice serves as a model for virus-induced encephalitis and hippocampal damage. C-type lectin domain family 12 member A (CLEC12A) is an inhibitory receptor, which modulates immune responses during inflammatory processes. However, the role of CLEC12A during neurotropic virus infections remains unclear. In this study, CLEC12A-deficient (CLEC12A^-/-) and wild type C57BL/6 mice were infected with TMEV. Neuroinflammatory responses, viral load, and immune cell infiltration were analyzed using immunohistochemistry, RT-qPCR, and flow cytometry. CLEC12A^-/- mice exhibited increased T cell sequestration in the brain, along with a higher expression of pro-inflammatory cytokine (TNF-α, IL-1β) and antigen presentation genes (CD11c, CD80, MHC-I) during acute infection. This led to an improved viral clearance in the hippocampus. CLEC12A deficiency also activates splenic CD4⁺ T cells and CD8⁺ cytotoxic T cells upon infection. Despite increased peripheral T cell activation and neuroinflammation, CLEC12A^-/- mice displayed less hippocampal damage with improved neuronal and axonal integrity. In conclusion, CLEC12A signaling in C57BL/6 mice contributes to suppressive immune modulation, delaying viral elimination and exacerbating brain damage during acute neurotropic virus infection.