Resident and infiltrating central nervous system APCs regulate the emergence and resolution of experimental autoimmune encephalomyelitis

During experimental autoimmune encephalomyelitis (EAE), autoreactive Th1 T cells invade the CNS. Before performing their effector functions in the tar get organ, T cells must recognize Ag presented by CNS APCs. Here, we invest igate the nature and activity of the cells that present Ag within the CNS d uring myelin oligodendrocyte glycoprotein-induced EAE, with the goal of und erstanding their role in regulating inflammation. Both infiltrating macroph ages (Mac-1(+) 'CD45(high)) and resident microglia (Mac-1(+) CD45(lnt)) exp ressed MHC-II, B7-1, and B7-2. Macrophages and microglia presented exogenou s and endogenous CNS Ags to T cell lines and CNS T cells, resulting in IFN- gamma production. In contrast, Mac-1(-) cells were inefficient APCs during EAE. Late in disease, after mice had partially recovered from clinical sign s of disease, there was a reduction in Ag-presenting capability that correl ated with decreased MHC-II and B7-1 expression. Interestingly, although CNS APCs induced T cell cytokine production, they did not induce proliferation of either T cell lines or CNS T cells. This was attributable to production by CNS cells (mainly by macrophages) of NO. T cell proliferation was resto red with an NO inhibitor, or if the APCs were obtained from inducible NO sy nthase-deficient mice. Thus, CNS APCs, though essential for the initiation of disease, also play a down-regulatory role. The mechanisms by which CNS A PCs limit the expansion of autoreactive T cells in the target organ include their production of NO, which inhibits T cell proliferation, and their dec line in Ag presentation late in disease.