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A. Terajewicz, D.E. Faunce, H.–H. Lin, S. Gordon, J. Stein–Streilein; F4/80 protein expression by APC is required for generation of T regulatory cells in ACAID and low dose oral tolerance . Invest. Ophthalmol. Vis. Sci. 2004;45(13):2309.
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Purpose: Anterior Chamber Associated Immune Deviation (ACAID) and low dose (ld) oral tolerance (OT) are models of peripheral tolerance in which efferent CD8+ T regulatory (Tr) cells are generated. The ACAID inducing signal that leaves the eye and travels to the spleen post anterior chamber (a.c.) inoculation of antigen is an F4/80+ APC. We have shown that the F4/80+ APC accumulates in the marginal zone of the spleen seven days post a.c. inoculation. The F4/80 molecule is commonly identified as a marker for mouse macrophages and although the protein was identified two decades ago its function is unknown. The purpose of our study was to test the postulate that the F4/80 protein has a role in peripheral tolerance models [ACAID, (ld) OT] that generate CD8+ Tr cells. Methods: Endotoxin free ovalbumin (OVA) was inoculated a.c. or orally (gavage) to wild–type (WT) or F4/80 knockout (KO) mice (with or without F4/80 cell reconstitution). Tolerance to the antigen was assessed in a delayed type hypersensitivity assay (DTH) or local adoptive transfer DTH assay (LAT–DTH). All cell enrichments were confirmed by flow cytometry. Results: Following ACAID or (ld) OT induction, WT but not F4/80 KO mice produced CD8+ Tr cells that suppressed DTH responses. When F4/80 KO mice where reconstituted with enriched F4/80+ bone marrow–derived antigen presenting cells or F4/80+ adherent spleen cells, CD8+ Tr cells were generated in both models of tolerance. Conclusions:While it is known that the eye is an immune privileged site and the gut is not, the eye and the gut share some aspects of tolerance induction. If antigen is delivered into either site, antigen specific efferent CD8+ Tr cells are generated. Moreover, both ACAID and ld OT models are dependent on the expression of the F4/80 protein on their APC to generate efferent CD8+ Tr cells. Thus a common mechanism for the induction of CD8+ Tr cells is shared by the eye and gut.
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