Ly6Chi monocytes govern cerebral toxoplasmosis

Abstract

Infection of the central nervous system (CNS) with the intracellular parasite Toxoplasma gondii (T. gondii) is followed by activation of resident cells and recruitment of immune cells from the periphery. We were interested to analyze the phenotype, function and dynamics of myeloid cell-subsets. Here we show, that depletion of CCR2+ Ly6Chi inflammatory monocytes, a subset of recruited myeloid cells, results in decreased survival, suggesting their critical importance in host defense against T. gondii infection. Moreover, CCR2+ Ly6Chi monocytes produce pro-inflammatory mediators, such as IL-1a, IL-1b, iNOS, TNF and ROS, confirming their anti-parasitic role. Furthermore, we demonstrate by adoptive transfer that inflammatory monocytes develop into two distinct subpopulations: CCR2+ Ly6Cint F4/80int and CCR2+ Ly6Cneg F4/80hi. The CCR2+ Ly6Cint F4/80int cells perform dendritic cell like functions such as interacting with T cells via MHC I and MHC II molecules. The CCR2+ Ly6Cneg F4/80hi cell subset displays elevated phagocytic capacity and upregulates TREM2. Finally, we show that recruitment of Ly6Chi monocytes to the CNS is mediated by selectins. These results indicate the crucial role of recruited Ly6Chi monocytes upon cerebral toxoplasmosis, unraveling the dynamics and function of further differentiated mononuclear cell subsets in parasite control and immune regulation in the CNS.