Levels of Foxp3 in Regulatory T Cells Reflect Their Functional Status in Transplantation

Abstract

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. In this study, 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.

UV light crosslinking regresses mature corneal blood and lymphatic vessels and promotes subsequent high-risk corneal transplant survival

“…It is reported that CD4 + CD25 + FoxP3 + Tregs can be uniquely induced when orthotopic corneal allografts are transplanted to the eye 51, 52, 53. Furthermore, Tregs support long‐term corneal allograft survival 54, 55, 56, 57. Tregs can respond to interleukin‐17A (a proinflammatory cytokine), suppress the efferent arm of the immune response, and then enhance corneal allograft survival 55…”

Mesenchymal Stem Cell Therapy Promotes Corneal Allograft Survival in Rats by Local and Systemic Immunomodulation

“…However, as detailed by Chauhan et al (31), predicting and/or correlating allograft fate solely on the basis of Treg frequency may lead to inaccurate conclusions. It is therefore important to measure the levels of Foxp3 expression in parallel, with evidence that higher levels of Foxp3 expression are directly associated with an increased ability of Tregs to prevent graft rejection.…”

“…There was also a clearly higher percentage of splenic CD4þFoxp3þ Tregs following third-party MSC treatment ( Figure 6A). Equally as important as the frequency of Foxp3-expressing Tregs is the level of Foxp3 expressed by these cells (31). To investigate this, we gated on the cell population of interest by forward scatter (FSC) and side scatter (SSC) parameters followed by doublet exclusion and subsequent gating based on expression of CD4 and CD25 ( Figure 6B).…”

CD4+ T cells from multiple sclerosis patients respond to a commensal‐derived antigen

“…CD4 + CD25 + T regs isolated from MS patients were found to have significantly reduced expression of Foxp3 23. Since the level of Foxp3 expression can impact suppressive function in vivo, 24 the ability of PSA to increase the MFI of Foxp3 provides further evidence that PSA could potentially reverse the functional defects characterized in the T reg population of MS patients. We also show that PSA can significantly increase the production of IL‐10.…”