Corneal antigen-presenting cells: diversity, plasticity, and disguise: the Cogan lecture.

The study of antigen-presenting cells (APCs) is important for all immune-mediated disorders because these cells are not only the “sentinels” of the immune system for detection of foreign antigens, but they also play a critical role in tolerance induction to both selfand foreign antigens. In addition to their role in immune surveillance and induction of antigenspecific immune reactivity and tolerance, APCs can also serve an important role in innate immunity due to their capacity to respond acutely to inflammatory insults or “danger” signals in peripheral tissues. APCs can be divided into two functional groups: “professional” and “nonprofessional” APC. Professional APCs are thus called because they generally have a high constitutive expression of major histocompatibility complex (MHC) class II antigen, as well as costimulatory molecules, and hence are capable of efficient provision of both signals for T-cell priming. Examples of professional APCs include dendritic cells (DCs), macrophages, B cells, and epithelial Langerhans cells (LCs). In contrast to professional APCs, nonprofessional APCs have a low T-cell stimulatory capacity because their constitutive expression of MHC class II antigen and costimulatory molecules is low; however, under certain circumstances (as may occur in inflammation) these cells may also provide requisite signals for T-cell priming. Examples of nonprofessional APCs include vascular endothelial and certain mesenchymal cells. The most potent APCs in most tissues are DCs and LCs. Indeed, these cells are also known to serve as the professional APCs of the cornea and ocular surface. Their activation and recruitment to the cornea has been associated with loss of “immune privilege” in the anterior segment, exacerbation of herpetic and Pseudomonas keratitis, and amplification of transplant immunity. The focus of our laboratory has been on studying the molecular factors that mobilize corneal APCs. Specifically, we have been interested in determining the (1) adhesion factors at the level of the limbal vascular endothelium that are required for leukocyte recruitment from the intravascular compartment into the tissue matrix, (2) chemotactic signals that are critical for recruiting limbal APCs into the cornea, (3) phenotypic and functional alterations to APCs associated with their maturation in the inflamed corneal microenvironment, (4) molecular factors that allow for mobilization and egress of mature APCs into lymphatics, and (5) critical costimulatory factors required for T-cell priming in lymphoid organs. Most of our studies to date addressing the above questions have exploited the orthotopic corneal transplant model in the mouse. This model, while technically challenging, offers distinct advantages for the study of corneal immunobiology. First, to the extent that they have been studied, the cellular and molecular mechanisms of murine corneal allotransplant rejection largely resemble those of the human. Second, because of its clarity, the cornea is a perfect tissue for directly observing immunoinflammatory responses without the need to sacrifice the eye or the animal. Third, because of its easy accessibility, the cornea is an optimal tissue for atraumatic local immune modulation. Fourth, known immunogenetic differences between inbred strains of mice make this corneal model an optimal method for delineating the contribution of donor versus host-derived cells to the generation of the immune response to corneal antigens. Finally, and importantly, the study of corneal graft (by far the most common form of transplantation) immunology remains a priority because of the propensity of corneal grafts to be rejected when they are grafted onto inflamed host beds.