Impaired Function of Peripherally Induced Regulatory T Cells in Hosts at High Risk of Graft Rejection

Abstract

Regulatory T cells (Tregs) are crucial for allograft survival. Tregs can be divided into thymus-derived natural Tregs (tTregs) and peripherally-derived induced Tregs (pTregs). Here, we determine whether the suppressive function of Treg subsets is hampered in hosts who are at high risk for rejecting their graft. To induce graft beds that promote high risk of transplant rejection, intrastromal corneal sutures were placed two weeks prior to the transplant procedure in mice. We demonstrate that in high-risk recipients the frequencies and function of pTregs (but not tTregs) are suppressed. Reduced function of pTregs correlated with decreased expression of CTLA-4, interleukin-10, and transforming growth factor-β. Adoptive transfer of pTregs from mice at low risk of subsequent graft rejection is able to rescue graft survival in recipients that are at high risk of rejecting their grafts. Our data suggest that impaired function of pTregs, but not tTregs, mediates the loss of immune tolerance and promotes allograft rejection.

Regulatory T cells promote corneal endothelial cell survival following transplantation via interleukin-10

“…status of Tregs demonstrates significant plasticity, and is determined in part by cues from their microenvironment. 23 We note that IL-10 has been reported to expand Foxp3 + Tregs, to promote CTLA-4 expression by Tregs and increase their suppressive function. 23 We note that IL-10 has been reported to expand Foxp3 + Tregs, to promote CTLA-4 expression by Tregs and increase their suppressive function.…”

“…Previous work from our group has shown that Tregs derived from both low-risk and high-risk corneal allograft recipients effectively suppress the proliferation of effector CD4 + CD25 − T cells, although Tregs derived from low-risk hosts exhibit 20% more suppressive capacity relative to Tregs from high-risk hosts 23. Indeed, we show that both Tregs from low-risk and high-risk hosts are effective in protecting CEnCs, with a greater cytoprotective capacity demonstrated by Tregs derived from low-risk hosts.…”

“…23 We thus next investigated the role of IL-10 in mediating the cytoprotective function of Tregs. Previous work from our laboratory has demonstrated that Tregs derived from high-risk graft recipients secrete significantly lower levels of IL-10 compared to their counterparts derived from low-risk hosts.…”

“…9,10 Substantial progress has been made in determining the mechanisms by which host factors, such as recipient bed vascularity and inflammation, influence the immune response to corneal allografts. 16 Studies performed by our laboratory [17][18][19][20][21][22][23][24] and others [25][26][27] indicate the critical contribution of Foxp3 + Tregs to immune tolerance in the setting of corneal transplantation. 16 Studies performed by our laboratory [17][18][19][20][21][22][23][24] and others [25][26][27] indicate the critical contribution of Foxp3 + Tregs to immune tolerance in the setting of corneal transplantation.…”

A New Immunotherapy Using Regulatory T-Cells for High-Risk Corneal Transplantation

“…This differentiation has permitted studies evaluating these distinct Treg subsets in a variety of immunopathologies. In the current study, we used a mouse model of corneal transplantation 17) 21) 22) to delineate the differential function and susceptibility of tTregs and pTregs from allograft recipients, including healthy (low-risk) hosts with normal immune homeostatic mechanisms who develop allotolerance naturally and ʻhigh-riskʼ hosts with inflamed graft beds who are prone to swift rejection of their transplants 22) . Our study had clearly showed impaired function of pTregs, but not tTregs, mediates the loss of immune tolerance and promotes allograft rejection 22) .…”