With the advent of powerful immunosuppression drugs, acute allograft rejection is rare now in the clinic and the short-term transplant survival hs been excellent. However, long-term transplant survival is also rare and most allografts are continuously lost to rejection as time progresses. It is undeniable that there remain significant barriers to long-term graft acceptance. We recently discovered that Foxp3+ Tregs, a cell type dedicated to immune regulation and critically involved in transplant tolerance, can be driven to exhaustion by a costimulatory molecule OX40. The exhausted Tregs readily lose their regulatory functions, acquire typical exhaustion markers such as PD-1, Tim-3, and KLRG1, and become susceptible to apoptosis. We identified a new transcription factor Baft3 through transcriptional profiling and believed to be involved in Treg exhaustion. Batf3 is strongly induced by OX40 and closely associated with the development of exhausted Tregs. We provide compelling data that Baft3 physically binds to the promoter region of Foxp3 and actively suppresses Foxp3 expression. Based on this, we hypothesized that Treg exhaustion is a preciously unrecognized fate of Foxp3+ Tregs and that Treg exhaustion is transcriptionally regulated in which Batf3 plays a central role. Understanding the mechanisms of Batf3 induction by OX40 and how Batf3 drives Tregs to exhaustion is the central focus of this proposal. We believe that the proposed studies will unravel novel mechanisms of tolerance resistance and may lead to the development of new therapies in the induction of transplant tolerance. In addition, findings from these studies will have broad impact on other immune-mediated diseases, such as cancer therapies, autoimmunity, and vaccination development.

Public Health Relevance

The potential of organ transplantation as a life-saving procedure is limited by drug-associated toxicities and chronic progressive graft loss. Our project is designed to uncover the underlying mechanisms that hinder transplant survival. This line of inquiry will open new therapeutic opportunities in the development of greatly improved therapies for patients with organ transplants as well as treatment of other immune mediated diseases including bone marrow transplantation, autoimmune diabetes, and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI106200-04
Application #
9206474
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
2014-02-01
Project End
2019-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
4
Fiscal Year
2017
Total Cost
$393,750
Indirect Cost
$143,750
Name
Methodist Hospital Research Institute
Department
Type
Other Domestic Non-Profits
DUNS #
185641052
City
Houston
State
TX
Country
United States
Zip Code
77030
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Fischer, Julius Clemens; Otten, Vera; Kober, Maike et al. (2017) A20 Restrains Thymic Regulatory T Cell Development. J Immunol 199:2356-2365
Wu, Jie; Zhang, Hedong; Shi, Xiaomin et al. (2017) Ablation of Transcription Factor IRF4 Promotes Transplant Acceptance by Driving Allogenic CD4+ T Cell Dysfunction. Immunity 47:1114-1128.e6
Li, Junhui; Chen, Shuqiu; Xiao, Xiang et al. (2017) IL-9 and Th9 cells in health and diseases-From tolerance to immunopathology. Cytokine Growth Factor Rev 37:47-55
Xiao, Xiang; Shi, Xiaomin; Fan, Yihui et al. (2016) The Costimulatory Receptor OX40 Inhibits Interleukin-17 Expression through Activation of Repressive Chromatin Remodeling Pathways. Immunity 44:1271-83
Xiao, Xiang; Shi, Xiaomin; Fan, Yihui et al. (2015) GITR subverts Foxp3(+) Tregs to boost Th9 immunity through regulation of histone acetylation. Nat Commun 6:8266
Chen, Wenhao; Ghobrial, Rafik M; Li, Xian C (2015) The Evolving Roles of Memory Immune Cells in Transplantation. Transplantation 99:2029-37