Studies on the induction of anterior chamber-associated immune deviation (ACAID). III. Induction of ACAID depends upon intraocular transforming growth factor-beta

Abstract

Delayed hypersensitivity (DH), the prototypical form of cell-mediated immune responsiveness, is mediated with the participation of considerable nonspecific inflammation which necessarily disrupts the anatomic integrity of involved and adjacent tissues. Damage of this type is of minor consequence to many visceral and cutaneous organs, but is of devastating consequence for organs such as the eye and the brain. At least in the case of the eye, the organ is remarkably adept at regulating the immune system's ability to respond to intraocular antigens by selectively down-regulating both the induction and expression of delayed hypersensitivity while leaving other effector modalities intact. This ability of the eye to selectivity down-regulate systemic DH responses to intracamerally inoculated antigens is known as anterior chamber-associated immune deviation (ACAID) and is mediated in part by antigen-specific regulatory T cells. Recent work suggests that macrophages (M phi) that reside in the iris and ciliary body can migrate out of an antigen-bearing eye and activate regulatory T cells within the spleen. In an effort to understand the mechanism by which intraocular M phi interact with antigen in the anterior chamber of the eye (AC) and subsequently induce splenic regulatory cells in ACAID, we have investigated what role, if any, the AC microenvironment itself plays in ACAID induction. The results reveal that CD45- parenchymal iris/ciliary cells secrete a soluble factor(s) locally and into the aqueous humor which endows resident, mature M phi with ACAID-inducing capabilities. Mice receiving infusions of these altered, antigen-pulsed M phi are incapable of mounting a significant DH response following immunization with antigen in adjuvant. Importantly, the ACAID-inducing effect is achieved when conventional, extraocular M phi are exposed in vitro to a soluble factor present in aqueous humor or culture SN from iris and ciliary body cells. Further investigations into the identity of this factor reveal it to be transforming growth factor-beta (TGF-beta). The role of TGF-beta in the generation of ACAID, as well as the implications of these findings to an understanding of immunologic privilege in general, are discussed.