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-Treated APCs and Its Relevance to Their Immune Deviation-Promoting Properties1
Department of Ophthalmology, Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114
APCs deployed within iris/ciliary body are responsible for
promoting anterior chamber-associated immune deviation following
injection of Ag into the eye. TGF
-2, a constituent of the ocular
microenvironment, converts conventional APCs that are pulsed with Ag
into cells that induce immune deviation when injected into naive mice.
TGF-2-treated APCs under-express IL-12 and CD40, and over-express
active TGF. We have examined transcriptional changes within
macrophage hybridoma no. 59, which promotes Th1 cell differentiation,
and TGF-2-treated no. 59 as well as macrophage hybridoma no. 63,
both of which induce immune deviation similar to anterior
chamber-associated immune deviation. Immune deviation-inducing
hybridomas up-regulated expression of thrombospondin, TGF, IFN-
and , murine macrophage elastase, and macrophage-inflammatory
protein-2 genes, while down-regulating expression of the genes
for NF-
B and CD40. Based on the known properties of these gene
products, a model is proposed in which these gene products, alone and
through interacting signaling pathways, confer upon conventional APCs
the capacity to create and surround themselves with an immunomodulatory
microenvironment. The model proposes that the pleiotropic effects of
thrombospondin are primarily responsible for creating this
microenvironment that is stabile, rich in active TGF and IFN- and
, deficient in IL-12, and chemoattractant via
macrophage-inflammatory protein-2 for NK T cells. It is further
proposed that presentation of Ag to T cells in this microenvironment
leads to their differentiation into regulatory cells that suppress Th1
cell-dependent immunogenic inflammation.
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