Person:

Dana, Reza

Foxp3 expressing CD4+CD25+ regulatory T cells (Tregs) have been shown to prevent allograft rejection in clinical and animal models of transplantation. However, the role of Foxp3 in regulating Treg function, and the kinetics and mechanism of action of Tregs in inducing allograft tolerance in transplantation, are still not fully understood. Thus, we investigated the kinetics and function of Tregs in a mouse model of orthotopic corneal transplantation, the most common form of tissue grafting worldwide. Here using in-vitro functional assays and in-vivo Treg adoptive transfer assays, we show that far more relevant than Treg frequency is their level of Foxp3 expression, which is directly associated with the potential of Tregs to prevent allograft rejection by producing regulatory cytokines and suppressing effector T cell activation. In addition, our data clearly demonstrate that Tregs primarily suppress the induction of alloimmunity in regional draining lymph nodes, rather than suppressing the effector phase of the immune response in the periphery. These findings provide new insights on Treg dynamics in transplantation which are crucial for designing therapeutic strategies to modulate Treg function, and to optimize Treg-based cell therapies for clinical translation.

Regulatory T cells (Tregs) are instrumental in the induction and maintenance of tolerance, including in transplantation. Tregs induce allotolerance by interacting with antigen-presenting cells (APC) and T cells, interactions that require their proper homing to the lymphoid tissues. Using a well characterized model of corneal allotransplantation, we demonstrate here that Tregs in the draining LN of allograft acceptors, but not rejectors, colocalize with APC in the paracortical areas and express high levels of C-C motif chemokine receptor 7 (CCR7). In addition, we show that Treg expression of CCR7 is important not only for Treg homing to the draining LN, but also for optimal Treg suppressive function. Finally, we show that Tregs augmented for CCR7 expression by their ex vivo stimulation with the CCR7-ligand CCL21 show enhanced homing to the draining LN of allograft recipients and promote transplant survival. Together, these findings suggest that CCR7 expression is critical for Treg function and migration, and that conditioning of Treg for maximal CCR7 expression may be a viable strategy for promoting allograft survival.

Corneal transplantation is one of the most prevalent and successful forms of solid tissue transplantation. Despite favorable outcomes, immune-mediated graft rejection still remains the major cause of corneal allograft failure. While ‘low risk’ graft recipients with uninflamed graft beds enjoy a success rate of approximately 90%, the rejection rates in inflamed graft beds or ‘high risk’ recipients often exceed 50% despite maximal immune suppression. In this review we discuss the critical facets of corneal alloimmunity, including immune and angiogenic privilege, mechanisms of allosensitization, cellular and molecular mediators of graft rejection, and allotolerance induction.