Two different regulatory T cell populations that promote corneal allograft survival

Corneal transplantation has been performed successfully on humans for over 100 years and on animals since 1837.1,2 Corneal transplants are routinely performed without HLA typing or the use of systemic immunosuppressive drugs. Patients who require corneal transplants because of developmental anomalies of the cornea, which are not associated with inflammation of the ocular surface, have exceptionally high success rates that often reach 90%.3 This apparent defiance of the laws of transplantation was recognized over 50 years ago in animal studies by Billingham and Medawar.4,5 Medawar recognized the profound implications of these observations and coined the term “immune privilege” to reflect the unique immunologic properties of the anterior chamber (AC) and the cornea.5 The immune privilege of corneal allografts can be defined mathematically if one considers the fate of corneal allografts in rodents that receive corneal allografts that are mismatched at the entire major histocompatibility complex and multiple minor loci. In rat and mouse models of penetrating keratoplasty, 50% of such corneal allografts survive long term.6–8 By contrast, skin and heart allografts undergo 100% immune rejection in such hosts. Three basic factors contribute to the immune privilege of corneal allografts: the blockade in the induction of the immune response to the alloantigens expressed on the corneal allograft, the generation of T regulatory cells (Tregs) that suppress the allodestructive immune responses against the donor alloantigens, and the expression of apoptosis-inducing molecules on the cell membranes of corneal cells that delete alloreactive T cells at the graft/host interface. Antigens introduced into the AC elicit a unique form of systemic immune tolerance termed anterior chamber–associated immune deviation (ACAID), which culminates in the antigen-specific suppression of delayed-type hypersensitivity (DTH).9–11 Orthotopic corneal allografts are placed directly over the AC of the eye, and it has been proposed that this juxtapositioning of the orthotopic corneal allograft with the AC facilitates the sloughing or shedding of corneal alloantigens into the AC, which in turn would induce ACAID.10 Several observations support this hypothesis. Rodents with long-term clear corneal allografts display an antigen-specific suppression of DTH responses that resembles the suppression of DTH found in ACAID.10–12 Moreover, manipulations that inhibit the induction of ACAID, such as splenectomy, ablation of NK T cell or γδ T cell populations, invariably lead to an increased tempo and incidence of corneal allograft rejection.10,11,13–16 Injection of donor alloantigenic cells into the AC before corneal transplantation induces ACAID and results in a significant enhancement of corneal allograft survival in both the rat and mouse models of penetrating keratoplasty.17,18 With this in mind, we embarked on a series of experiments designed to compare and contrast maneuvers that affect ACAID with those that are known to influence the immune privilege of corneal allografts. The underlying hypothesis predicted that the Tregs that supported ACAID and corneal allograft survival were one in the same. However, the results indicate that two different forms of immune tolerance are involved in ACAID and corneal allograft survival.