Control of delayed-type hypersensitivity by ocular- induced CD8+ regulatory t cells.

The immunoregulatory pathway from the eye to the peri - pheral immune system is comprised of the iris, ciliary body, circulation, thymus and spleen, and is influenced by the sympathetic nervous system. At the splenic end of this pathway are antigen-specific CD8+ regulatory T cells (Tregs) that mediate directly the suppression of T cells that effect delayedtype hypersensitivity (DTH). Here we review investigations that demonstrate: (i) the injection of antigen into the anterior chamber (AC) attracts circulating monocytic cells to the iris/ciliary body that recirculate to the thymus and spleen. In the thymus, ocular-influenced monocytic cells activate natural killer T (NKT) cells that migrate to the spleen where, in concert with the ocular-influenced monocytic emigrants, they (ii) activate CD4+ and CD8+ immunoregulatory T cells. (iii) The generation of the CD8+ Tregs is dependent on NKT cells in the thymus and the periphery that are influenced by the sympathetic nervous system. (iv) The suppression of DTH by the AC-induced CD8+ Tregs is dependent on the cytokines transforming growth factor-Beta and interferon-gamma and is restricted by the expression of major histocompatibility complex-associated Qa-1b antigens. In aggregate, this oculothymic- splenic pathway is a well-controlled response to ocular injury that utilizes a systemic response to antigen that may protect ocular tissue and systemic tissue.