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Department of Epidemiology and Public Health and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
During experimental autoimmune encephalomyelitis (EAE),
autoreactive Th1 T cells invade the CNS. Before performing their
effector functions in the target organ, T cells must recognize Ag
presented by CNS APCs. Here, we investigate the nature and activity of
the cells that present Ag within the CNS during myelin oligodendrocyte
glycoprotein-induced EAE, with the goal of understanding their role in
regulating inflammation. Both infiltrating macrophages
(Mac-1+CD45high) and resident microglia
(Mac-1+CD45int) expressed MHC-II, B7-1, and
B7-2. Macrophages and microglia presented exogenous and endogenous CNS
Ags to T cell lines and CNS T cells, resulting in IFN-
production.
In contrast, Mac-1- cells were inefficient APCs during
EAE. Late in disease, after mice had partially recovered from clinical
signs of disease, there was a reduction in Ag-presenting capability
that correlated 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 restored with an NO
inhibitor, or if the APCs were obtained from inducible NO
synthase-deficient mice. Thus, CNS APCs, though essential for the
initiation of disease, also play a down-regulatory role. The mechanisms
by which CNS APCs limit the expansion of autoreactive T cells in the
target organ include their production of NO, which inhibits T cell
proliferation, and their decline in Ag presentation late in
disease.
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