Role of CD4+ and CD8+ T Cells in Allorecognition: Lessons from Corneal Transplantation

Abstract

Corneal transplantation represents an interesting model to investigate the contribution of direct vs indirect Ag recognition pathways to the alloresponse. Corneal allografts are naturally devoid of MHC class II+ APCs. In addition, minor Ag-mismatched corneal grafts are more readily rejected than their MHC-mismatched counterparts. Accordingly, it has been hypothesized that these transplants do not trigger direct T cell alloresponse, but that donor Ags are presented by host APCs, i.e., in an indirect fashion. Here, we have determined the Ag specificity, frequency, and phenotype of T cells activated through direct and indirect pathways in BALB/c mice transplanted orthotopically with fully allogeneic C57BL/6 corneas. In this combination, only 60% of the corneas are rejected, while the remainder enjoy indefinite graft survival. In rejecting mice the T cell response was mediated by two T cell subsets: 1) CD4+ T cells that recognize alloantigens exclusively through indirect pathway and secrete IL-2, and 2) IFN-γ-producing CD8+ T cells recognizing donor MHC in a direct fashion. Surprisingly, CD8+ T cells activated directly were not required for graft rejection. In nonrejecting mice, no T cell responses were detected. Strikingly, peripheral sensitization to allogeneic MHC molecules in these mice induced acute rejection of corneal grafts. We conclude that only CD4+ T cells activated via indirect allorecognition have the ability to reject allogeneic corneal grafts. Although alloreactive CD8+ T cells are activated via the direct pathway, they are not fully competent and cannot contribute to the rejection unless they receive an additional signal provided by professional APCs in the periphery.

Quantification of allospecific and nonspecific corneal endothelial cell damage after corneal transplantation

“…CEC apoptosis mediated by CD4 þ T cells in a non-contact-dependent mechanism could be primarily promoted via secretion of apoptosis-inducing cytokines/molecules. In corneal transplantation, a major subset of CD4 þ T cells are T helper type 1 cells, 4 which are characterized by the expression of their signature cytokine IFN-g, and other proinflammatory cytokines such as TNF-a and IL-1. These proinflammatory cytokines (IFN-g, TNF-a, and IL-1) have been shown to induce apoptosis in CECs.…”

“…[1][2][3] Despite medical advances, immune rejection of corneal grafts remains the most frequent cause of corneal graft failure. 4 Several studies have shown that CD4 þ T cells are the major mediators of acute corneal graft rejection. Corneal endothelial cells (CECs) are the principal targets of alloimmunity in corneal transplantation, which primarily involves allospecific CD4 þ T cells attacking the graft endothelium.…”

“…Corneal endothelial cells (CECs) are the principal targets of alloimmunity in corneal transplantation, which primarily involves allospecific CD4 þ T cells attacking the graft endothelium. 4,5 The corneal endothelium is a monolayer of neural crestderived cells that line the posterior surface of the cornea. The pump and barrier functions of CECs maintain the corneal transparency.…”

Antigenicity and immunogenicity of allogeneic retinal transplants

“…Three nonexclusive explanations may account for this observation: (a) some evidence has been provided suggesting the possible presence of a very small population of T cells (3%) expressing CD8 intracellularly in CD8 KO mice (26), (b) some non-CD8 + T cells such as natural killer (NK) cells or double-negative T cells may secrete some IFN-γ (27,28), and (c) it is likely that some compensatory mechanisms are present in KO mice. For instance, we have observed previously that in CD4 KO mice one can find more CD4-independent CD8 T cells that produce their own IL-2, thereby compensating for the absence of CD4 + T cell help (29).…”

Bidirectional alloreactivity

“…50 Thus, corneal transplants can be done with only short-term, topical immunosuppression, partly due to anatomical restrictions of blood and lymph supply, but partly due to tolerogenic effects of MHC class II neg corneal DC. 51 This is associated with the lack of inflammatory CD4 + T cell direct alloresponse. On the other hand, indirect CD4 + T cell responses are regularly detected in mice recipients of fully allogeneic corneas.…”