Our laboratories have a long-standing interest in immune tolerance in transplantation, with a particular focus on regulatory T cells (Tregs). While Tregs expressing Foxp3 are required for normal immune homeostasis increasing data suggests that this lineage of cells may be unstable (e.g., as a result for example of inadequate IL-2, TCR and CD28 stimulation, or due to exposure to inflammatory cytokines), meaning that Tregs can revert/convert to effector T cells and thus contribute to loss of tolerance to self or to allografts. One of the key pathways controlling lymphocyte lineage specification and responsiveness is the PI3K pathway, which can be activated via CD28 and the IL-2R. While PI3K is essential for conventional T cell responses, over activation of the PI3K pathway dramatically inhibits Treg development. The primary regulator of PI3K activity in T cells is the lipid phosphatase PTEN (phosphatase and tensin homolog on chromosome 10). To investigate how PI3K controls Tregs, we created mice with PTEN deleted specifically in Tregs by breeding mice with a PTENfl/fl allele with Foxp3-YFP-Cre knock-in animals to generate PTEN-DTreg mice. Surprisingly, although these mice have elevated numbers of Tregs, a high proportion of those cells are CD25- and CD62Llo, and the animals are susceptible to induced autoimmunity and ultimately develop a severe polyclonal lymphoproliferative disorder. Interestingly, preliminary studies suggest that PTEN-deficient Tregs may have profound metabolic alterations, including over-reliance on glycolysis (vs. oxidative metabolism) for energy. Moreover, inhibition of glycolysis restores CD25 levels to normal. This has led us to formulate the hypothesis that PI3K activity induced via inflammation may disrupt Treg homeostasis due to reduced cytokine receptor expression, altered metabolism and apparent loss of regulatory capacity. Our goals are to determine how PI3K in Tregs controls Treg homeostasis and whether drug targeting of the PI3K pathway can stabilize Tregs. To do so, we have three aims.
In Aim #1, we will use fate mapping mice to examine how PTEN loss alters Treg stability and function under homeostatic conditions, and in a well characterized model of autoimmunity.
In Aim #2, we will determine the mechanism by which PI3K controls CD25 expression, examine how loss of PTEN alters Treg metabolism, define what role these changes play in Treg homeostasis and stability, and identify drugs which modulate metabolism that can be used to stabilize Tregs in vitro.
In Aim #3, we will apply these findings, and pharmacologic manipulation to transplantation models, including a humanized mouse model, to develop means to optimize Treg stability and function. Together, these studies will yield new insights into Treg signaling pathways and provide potential therapeutics strategies to enhance immune tolerance.

Public Health Relevance

A specific class of T lymphocytes, known as regulatory T cells, are important for controlling the rejection of organ and tissue transplants and for preventing autoimmune disease. The research proposed will examine how a cell signaling pathway, called the PI3K pathway, regulates the development and function of regulatory T cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL018646-40
Application #
9609540
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Schwartz, Lisa
Project Start
Project End
2020-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
40
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Gonzalez-Nolasco, Bruno; Wang, Mengchuan; Prunevieille, Aurore et al. (2018) Emerging role of exosomes in allorecognition and allograft rejection. Curr Opin Organ Transplant 23:22-27
Smith, R N; Matsunami, M; Adam, B A et al. (2018) RNA expression profiling of nonhuman primate renal allograft rejection identifies tolerance. Am J Transplant 18:1328-1339
Fan, Martin Y; Low, Jun Siong; Tanimine, Naoki et al. (2018) Differential Roles of IL-2 Signaling in Developing versus Mature Tregs. Cell Rep 25:1204-1213.e4
Benichou, Gilles; Prunevieille, Aurore (2018) Graft-derived exosomes. When small vesicles play a big role in transplant rejection. Am J Transplant 18:1585-1586
Marangoni, Francesco; Zhang, Ruan; Mani, Vinidhra et al. (2018) Tumor Tolerance-Promoting Function of Regulatory T Cells Is Optimized by CD28, but Strictly Dependent on Calcineurin. J Immunol 200:3647-3661
Fan, Martin Y; Turka, Laurence A (2018) Immunometabolism and PI(3)K Signaling As a Link between IL-2, Foxp3 Expression, and Suppressor Function in Regulatory T Cells. Front Immunol 9:69
Wang, Zhaohui; Louras, Nathan J; Lellouch, Alexandre G et al. (2018) Dosing optimization of CCR4 immunotoxin for improved depletion of CCR4+ Treg in nonhuman primates. Mol Oncol 12:1374-1382
Newton, Ryan H; Shrestha, Sharad; Sullivan, Jenna M et al. (2018) Maintenance of CD4 T cell fitness through regulation of Foxo1. Nat Immunol 19:838-848
Hotta, Kiyohiko; Oura, Tetsu; Dehnadi, Abbas et al. (2018) Long-term Nonhuman Primate Renal Allograft Survival Without Ongoing Immunosuppression in Recipients of Delayed Donor Bone Marrow Transplantation. Transplantation 102:e128-e136
Robinson, Kortney A; Orent, William; Madsen, Joren C et al. (2018) Maintaining T cell tolerance of alloantigens: Lessons from animal studies. Am J Transplant 18:1843-1856

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