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RE Cone, Y Wang, DL Foss, J O'Rourke, I Goldschneider; Cellular Pathways in ACAID: Evidence That Thymic NK T Cells Induce Splenic Regulatory T Lymphocytes . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2963.
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Purpose: Intracameral injection of antigen induces the appearance of antigen-specific, CD4-,CD8-, NK1.1+ thymocytes (AC-THY) that adoptively transfer Anterior Chamber-Associated Immune Deviation (ACAID). Recipients of AC-THY generate antigen-specific splenic T cells (AC-SPL) that induce or effect the regulation of delayed-type hypersensitivity (DTH). Here we used adoptive transfer assays to determine whether the AC-THY induce and/or generate splenic CD4+ and CD8+ (inducer, effector respectively) regulatory T cells. Methods: AC-THY and AC-SPL were obtained from Balb/c, C57Bl/6 or AKR X C57Bl/6 mice that received intracameral TNP-BSA or BSA or AC-THY and TNP-BSA + Freund's Complete Adjuvant sc. Mononuclear cells obtained from the peripheral blood of AC-injected transgenic GFP (C57Bl/6) mice 24hr after injection of TNP-BSA were injected iv into C57Bl/6, GFP- mice. The phenotype of GFP+ cells in the spleens and thymus of recipients was determined with phycoerythrin-monoclonal anti-F4/80 and anti-CD11c antibodies. The immunoregulatory effector activity of AC-SPL was determined by injection of AC-SPL into the footpad of TNP-BSA-senstized mice concurrent with epicutaneous picryl chloride (PCl). The afferent immunoregulatory activity of AC-SPL was determined by iv injection of AC-SPL into TNP-BSA-senstitized mice and epicutaneous challenge with PCL 1 week later. Monoclonal anti-LY5.1 or 5.2 antibodies and immunomagnetic beads were used to separate LY 5.1 and LY 5.2+ AC-SPL from LY 5.2+ recipients of LY 5.1+ AC-THY. Results: F4/80+,CD11c+ (dendritic) peripheral blood mononuclear cells from transgenic GFP mice receiving intracameral TNP-BSA were thymus seeking when injected into C57Bl/6 mice and F4/80+, CD11c- peripheral blood monoculear cells from AC-injected mice were spleen seeking. The recipients of AC-THY induced by homologous antigen produced CD8+ splenic immunoregulatory effector cells. LY5.2+ (C57Bl/6) TNP-BSA-sensitized recipients of Ly5.1+AC-THY (AKR X C57Bl/6) produced LY5.1-,Ly5.2+ splenic immunoregultory effector and inducer cells. Conclusion: The results support our belief that (i) in ACAID intracameral injection of antigen induces blood-borne dendritic cells that deliver antigen to the thymus (ii) thereby inducing thymic NK T cells that migrate to the spleen (iii) where they activate afferent and efferent immunoregulatory splenic T cells that were induced by systemic immunization.
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