Role of CCR7 in Facilitating Direct Allosensitization and Regulatory T-Cell Function in High-Risk Corneal Transplantation

Abstract

Chemokine receptor 7 (CCR7) is a key homing molecule for immune cell trafficking, including corneal antigen-presenting cell (APC) migration from the inflamed cornea to draining lymph nodes (LNs). Here, the authors investigated the effect of CCR7-facilitated donor APC trafficking on allosensitization, regulatory T-cell (Treg) function, and graft survival in corneal transplantation. CCR7(-/-) or wild-type (WT) allogeneic corneal grafts were transplanted onto the neovascularized high-risk recipient beds. Two weeks later, the frequency of directly alloprimed host T cells was measured by the IFN-gamma ELISPOT assay. Treg function was tested by a coculture suppression assay and an IFN-gamma ELISPOT assay. Kaplan-Meier analysis was performed to evaluate graft survival. The recipients of CCR7(-/-) grafts had fewer migrated donor APCs and lower frequency of IFN-gamma-producing T cells in the draining LNs. However, there was no statistically significant difference in transplant survival between recipients of CCR7(-/-) and those of WT grafts. Tregs from the CCR7(-/-) graft recipient group showed reduced regulatory potential for the suppression of proliferation of naive T cells and direct alloprimed T cells and expressed lower Foxp3 levels. In vitro studies confirmed that mature CCR7(+) major histocompatibility complex class II(+) CD86(+) graft-derived dendritic cells were critical for Treg function. Not only is CCR7-mediated donor-derived APC trafficking to the draining LNs important in the initiation of host T-cell priming, it is crucial for Treg-mediated tolerance.