Injection of antigen into the anterior chamber (AC) of the eye, animmunologically privileged site, is associated with the inductionof immune deviation, as evidenced by T helper cell (Th) 1 to Th2 cellpolarization. We recently demonstrated that AC-associated immunedeviation (ACAID) is a thymus-dependent phenomenon initiated by the formation of regulatory α,β T-cell receptor-positiveCD4⁻ CD8⁻ thymocytes(THYregs). In this study, the afferent and efferent limbsof this immunoregulatory loop were traced from peripheral blood to thethymus and then to the spleen by adoptive-transfer assays. The resultsdemonstrate that (1) F4/80⁺ CD1⁺ peripheralblood mononuclear cells from mice whose ACs were injected withtrinitrophenol-bovine serum albumin induce the appearance ofnatural killer (NK) 1.1⁺ THYreg innaïve recipients within 24 h of intravenous infusion; (2)these NK THYregs induce (or generate) suppressor-effector Tcells in the spleens of adoptive recipients; (3) thesesuppressor-effector spleen cells, but not the NK THYregsthemselves, directly inhibit the expression of delayed-typehypersensitivity in sensitized recipients; and (4) peripheral bloodmononuclear cells from AC-injected mice do not induce ACAID inthymectomized recipients. These results confirm our hypothesis thatACAID is a model of centrally induced dominant tolerance mediated byCD-1-dependent NK T cells of recent thymic origin. The results alsoprovide evidence of a novel tolerance induction pathway by whichblood-borne antigen-presenting cells generated by antigen injectioninto an immunologically privileged site transport antigen to the thymusand induce the formation and export of THYreg.