Astrocytic but not Microglial Antigen Presentation Shapes Protective Immunity to Toxoplasma gondii in the Brain

T cells play a pivotal role in orchestrating immune defense within the central nervous system (CNS) during many infections. Toxoplasma gondii, a brain-trophic protozoan parasite, establishes lifelong CNS infection that remains largely subclinical in immunocompetent hosts but can cause severe encephalitis in immunocompromised individuals. While CD8⁺ T cells are essential for controlling T. gondii during chronic infection through both cytokine production and cytolytic killing, the CNS-resident cells that functionally present antigen in the brain to promote T cell function or serve as cytolytic targets remain incompletely defined. Here, we investigated the contributions of CNS-resident macrophages and astrocytes, two key CNS-resident cell types, antigen presentation during chronic T. gondii infection. Using mice lacking MHCI or MHCII in CNS-resident macrophages, we found no impairment of immune responses or ability of the brain to control parasite, indicating dispensable function of resident macrophages as APCs during infection. However, deletion of MHCI on astrocytes led to deficits in parasite control, in turn promoting elevated CD4⁺ T cell cytokine production and recruitment of iNOS⁺ inflammatory monocytes. We observed increased presence of lytic parasite within the brain, which suggests that astrocyte MHCI may be necessary to control parasite replication throughout the CNS. Our findings underscore a previously underappreciated role for astrocytic MHCI within the CNS during infection and highlights the dispensability of CNS-resident macrophages to this process.