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- Title
Allograft rejection is restrained by short-lived TIM-3<sup>+</sup>PD-1<sup>+</sup>Foxp3<sup>+</sup> Tregs.
- Authors
Gupta, Shipra; Thornley, Thomas B.; Gao, Wenda; Larocca, Rafael; Turka, Laurence A.; Kuchroo, Vijay K.; Strom, Terry B.
- Abstract
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 graftinfiltrating, short-lived subset of Tregs can restrain rejection.
- Publication
Journal of Clinical Investigation, 2012, Vol 122, Issue 7, p2395
- ISSN
0021-9738
- Publication type
Academic Journal
- DOI
10.1172/JCI45138