Journal
JOURNAL OF IMMUNOLOGY
Volume 168, Issue 5, Pages 2264-2273Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.168.5.2264
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Funding
- NEI NIH HHS [EY 05678] Funding Source: Medline
- NATIONAL EYE INSTITUTE [R37EY005678, R01EY005678] Funding Source: NIH RePORTER
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APCs deployed within iris/ciliary body are responsible for promoting anterior chamber-associated immune deviation following injection of Ag into the eye. TGFbeta-2, a constituent of the ocular microenvironment, converts conventional AM that are pulsed with Ag into cells that induce immune deviation when injected into naive mice. TGFbeta-2-treated APCs under-express IL-12 and CD40, and over-express active TGFbeta . We have examined transcriptional changes within macrophage hybridoma no. 59, which promotes Th1 cell differentiation, and TGFbeta-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, TGFbeta, IFN-alpha and beta, murine macrophage elastase, and macrophage-inflammatory protein-2 genes, while down-regulating expression of the genes for NF-kappaB 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 TGFbeta and IFN-alpha and beta, 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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