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.
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.
|Kean, Leslie S; Turka, Laurence A; Blazar, Bruce R (2017) Advances in targeting co-inhibitory and co-stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy. Immunol Rev 276:192-212|
|Tanimine, Naoki; Turka, Laurence A; Priyadharshini, Bhavana (2017) Navigating T Cell Immunometabolism in Transplantation. Transplantation :|
|Alessandrini, Alessandro; Turka, Laurence A (2017) FOXP3-Positive Regulatory T Cells and Kidney Allograft Tolerance. Am J Kidney Dis 69:667-674|
|Wang, Zhaohui; Zheng, Qian; Zhang, Huiping et al. (2017) Ontak-like human IL-2 fusion toxin. J Immunol Methods 448:51-58|
|Zheng, Qian; Wang, Zhaohui; Zhang, Huiping et al. (2017) Diphtheria toxin-based anti-human CD19 immunotoxin for targeting human CD19+ tumors. Mol Oncol 11:584-594|
|Adam, B A; Smith, R N; Rosales, I A et al. (2017) Chronic Antibody-Mediated Rejection in Nonhuman Primate Renal Allografts: Validation of Human Histological and Molecular Phenotypes. Am J Transplant 17:2841-2850|
|Zuber, Julien; Sykes, Megan (2017) Mechanisms of Mixed Chimerism-Based Transplant Tolerance. Trends Immunol 38:829-843|
|Benichou, Gilles; Gonzalez, Bruno; Marino, Jose et al. (2017) Role of Memory T Cells in Allograft Rejection and Tolerance. Front Immunol 8:170|
|Purroy, Carolina; Fairchild, Robert L; Tanaka, Toshiaki et al. (2017) Erythropoietin Receptor-Mediated Molecular Crosstalk Promotes T Cell Immunoregulation and Transplant Survival. J Am Soc Nephrol 28:2377-2392|
|Hotta, Kiyohiko; Aoyama, Akihiro; Oura, Tetsu et al. (2016) Induced regulatory T cells in allograft tolerance via transient mixed chimerism. JCI Insight 1:|
Showing the most recent 10 out of 288 publications