Allograft rejection is restrained by short-lived TIM-3+PD-1+Foxp3+ Tregs

Harvard Medical School, Department of Medicine, The Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 06/2012; 122(7):2395-404. DOI: 10.1172/JCI45138
Source: PubMed


Tregs play a pivotal role in inducing and maintaining donor-specific transplant tolerance. The T cell immunoglobulin and mucin domain-3 protein (TIM-3) is expressed on many fully activated effector T cells. Along with program death 1 (PD-1), TIM-3 is used as a marker for exhausted effector T cells, and interaction with its ligand, galectin-9, leads to selective death of TIM-3+ cells. We report herein the presence of a galectin-9-sensitive CD4+FoxP3+TIM-3+ population of T cells, which arose from CD4+FoxP3+TIM-3- proliferating T cells in vitro and in vivo and were often PD-1+. These cells became very prominent among graft-infiltrating Tregs during allograft response. The frequency and number of TIM-3+ Tregs peaked at the time of graft rejection and declined thereafter. Moreover, these cells also arise in a tolerance-promoting donor-specific transfusion model, representing a pool of proliferating, donor-specific Tregs. Compared with TIM-3- Tregs, TIM-3+ Tregs, which are often PD-1+ as well, exhibited higher in vitro effector function and more robust expression of CD25, CD39, CD73, CTLA-4, IL-10, and TGF-β but not galectin-9. However, these TIM-3+ Tregs did not flourish when passively transferred to newly transplanted hosts. These data suggest that a heretofore unrecognized graft-infiltrating, short-lived subset of Tregs can restrain rejection.

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    • "These Tregs expressed T cell immunoglobulin and mucin domain-3 (TIM-3), which is commonly expressed on activated Th1 and Th17 cells [45]–[47]. Interestingly, although TIM-3+ Tregs could more potently inhibit effector T cells than TIM-3− Tregs in vitro and preferentially infiltrated skin allografts, they expressed PD-1 and were susceptible to galectin-9-mediated death and actually exhibited reduced potency upon adoptive transfer [44]. These data suggest that potent Tregs are carefully controlled by mechanisms that promote both their regulatory function and their clearance in vivo. "
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    ABSTRACT: Patients with autoimmune lymphoproliferative syndrome (ALPS) and lymphoproliferation (LPR) mice are deficient in Fas, and accumulate large numbers of αβ-TCR(+), CD4(-), CD8(-) double negative (DN) T cells. The function of these DN T cells remains largely unknown. The common γ subunit of the activating Fc receptors, FcRγ, plays an important role in mediating innate immune responses. We have shown previously that a significant proportion of DN T cells express FcRγ, and that this molecule is required for TCR transgenic DN T cells to suppress allogeneic immune responses. Whether FcRγ plays a critical role in LPR DN T cell-mediated suppression of immune responses to auto and allo-antigens is not known. Here, we demonstrated that FcRγ(+), but not FcRγ(-) LPR DN T cells could suppress Fas(+) CD4(+) and CD8(+) T cell proliferation in vitro and attenuated CD4(+) T cell-mediated graft-versus host disease. Although FcRγ expression did not allow LPR DN T cells to inhibit the expansion of Fas-deficient cells within the LPR context, adoptive transfer of FcRγ(+), but not FcRγ(-), DN T cells inhibited lymphoproliferation in generalized lymphoproliferative disease (GLD) mice. Furthermore, FcRγ acted in a cell-intrinsic fashion to limit DN T cell accumulation by increasing the rate of apoptosis in proliferated cells. These results indicate that FcRγ can confer Fas-dependent regulatory properties on LPR DN T cells, and suggest that FcRγ may be a novel marker for functional DN Tregs.
    PLoS ONE 06/2013; 8(6):e65253. DOI:10.1371/journal.pone.0065253 · 3.23 Impact Factor
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    • "Expression of Gal-9 in corneal cells was retained after corneal allo-transplantation, and Tim-3-expressing CD8+ T cells were present in grafts 4 weeks after transplantation but disappeared after 8 weeks after transplantation. Tim-3 has been known as a marker for exhausted effector T cells, and interaction with Gal-9 leads to selective death of Tim-3+ cells[52]. Therefore, our results might suggest that Gal-9 expressed in the corneal tissue eluminated Tim-3+CD8+ T cells. If Tim-3 or Gal-9 were blocked by injection of neutralizing mAbs in recipients of corneal allografts, the allografts became more vulnerable to rejection and had more infiltration of both CD4+ and CD8+ T cells. "
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    • "A recent study using mouse skin transplantation model showed that the presence of Tim-3+PD-1+ Tregs in situ were crucial for induction of tolerance and restraining allograft rejection [14]. To determine whether Tim-3+PD-1+ Tregs exist in human tumor tissues, we compared the expression of Foxp3 in Tim-3 single positive (Tim-3 SP), PD-1 single positive (PD-1 SP), Tim-3 and PD-1 double positive cells (DP) and Tim-3 and PD-1 double negative (DN) cells. "
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