Allograft rejection is restrained by short-lived TIM-3+PD-1+Foxp3+ Tregs
Open accessAbstract
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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A compensatory delayed expansion of Treg cells in response to inflammation is known to control immune responses and maintain peripheral tolerance in various disease systems.
“A similar compensatory delayed expansion of Treg cells in response to inflammation is known to control immune responses and maintain peripheral tolerance in various disease systems43.”
From Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation (2019) · cites this paper as [43]
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- Authors
- Gupta, S., Thornley, T. B., Gao, W., Larocca, R., Turka, L. A., Kuchroo, V. K., & Strom, T. B.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Strom, Terry B.
- Venue
- Journal of Clinical Investigation
- Published
- 2012-07-02
- Volume
- 122
- Issue
- 7
- Pages
- 2395-2404
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3386804
- OpenAlex
- W1982505108
- Cited by
- 139
- References
- 44
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 12 · 2023: 9 · 2022: 8 · 2021: 10 · 2020: 12 · 2019: 21 · 2018: 7 · 2017: 12 · 2016: 7 · 2015: 9 · 2014: 8 · 2013: 12 · 2012: 2
- FWCI
- 4.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Beth Israel Deaconess Medical Center
- National Institutes of Health (AI073748, AI041521, NS038037)
- U.S. Public Health Service (P0AIGF41521)
- Medical Research Council (MR/J006742/1)
- National Institute of Allergy and Infectious Diseases (AI-37691, R01AI037691, P01AI041521, AI 41521, P01AI073748)
- National Institute of Neurological Disorders and Stroke (P01NS038037, R01NS045937)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Health Sciences › Medicine › Transplantation › Renal Transplantation Outcomes and Treatments
- Keywords
- allograft rejection, regulatory T cells, TIM-3, PD-1, Foxp3, galectin-9, T cell exhaustion, transplantation tolerance, graft-infiltrating T cells, donor-specific T cells, CD4+ T cells
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, Animals, Cells, Cultured, Graft Rejection, Lymph Nodes, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Receptors, Virus, Spleen, Transplantation, Homologous, CD4 Antigens, Skin Transplantation, Apoptosis, Galectins, Cell Proliferation, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Programmed Cell Death 1 Receptor
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