T cells are pivotal players in the adaptive immune response. However, when continuously exposed to antigen, as in persistent infection or cancer, T cells lose effector function and ultimately become exhausted, leading to chronic infection or progressive disease. Recent therapeutic advances are based on reversing these natural mechanisms set in place to ?quiet? activated T cells during the resolution phase of an immune response, and in doing so, reinvigorate immune responses crippled by T cell exhaustion. However, response rates remain low in many settings; thus, additional strategies are needed. Crucial for developing such strategies is to identify new targetable pathways, which is currently hampered by our limited basic knowledge of the negative regulatory pathways that inhibit T cell activation. We recently discovered that the pseudokinase Trib1 is a novel negative regulator of T cell activation, which is induced upon T cell receptor (TCR) stimulation. Our overall goal is to determine the cellular and molecular mechanisms by which Trib1 regulates T cell responses. Our preliminary data generated both in vitro and in vivo suggest that in the absence of Trib1, T cells are hyper-activated and are better able to control chronic infections. Mechanistically, Trib1 appears to exert its effects on T cells via a novel mechanism of regulating NF-?B. Based on these preliminary data, our overarching hypothesis is that Trib1 suppresses signaling pathways that promote T cell activation and promotes immune cell exhaustion by limiting T cell effector function and B cell help. This hypothesis will be tested in two aims:
Aim 1 will define the cellular responses regulated by Trib1, and Aim 2 will determine the signaling pathways responsible for these findings. Our findings may lead to new insights into controlling T cell activation and exhaustion in multiple scenarios, including chronic infections and cancer, and in doing so, identify new avenues for therapeutic interventions.

Public Health Relevance

We recently discovered an important function for Tribbles, a protein best known for its role as an adapter in protein degradation, in T cell function. Our research will provide key insights into how Tribbles regulates T cell activation and exhaustion, and in doing so, may reveal new opportunities for therapeutic targeting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047833-17
Application #
9637296
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Prabhudas, Mercy R
Project Start
2000-08-01
Project End
2023-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
17
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Johnson, John L; Georgakilas, Georgios; Petrovic, Jelena et al. (2018) Lineage-Determining Transcription Factor TCF-1 Initiates the Epigenetic Identity of T Cells. Immunity 48:243-257.e10
Plikus, Maksim V; Guerrero-Juarez, Christian F; Ito, Mayumi et al. (2017) Regeneration of fat cells from myofibroblasts during wound healing. Science 355:748-752
Ryan, Russell J H; Petrovic, Jelena; Rausch, Dylan M et al. (2017) A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas. Cell Rep 21:784-797
Pajcini, Kostandin V; Xu, Lanwei; Shao, Lijian et al. (2017) MAFB enhances oncogenic Notch signaling in T cell acute lymphoblastic leukemia. Sci Signal 10:
Uljon, Sacha; Xu, Xiang; Durzynska, Izabela et al. (2016) Structural Basis for Substrate Selectivity of the E3 Ligase COP1. Structure 24:687-696
Stein, Sarah J; Mack, Ethan A; Rome, Kelly S et al. (2016) Trib2 Suppresses Tumor Initiation in Notch-Driven T-ALL. PLoS One 11:e0155408
Chiang, Mark Y; Wang, Qing; Gormley, Anna C et al. (2016) High selective pressure for Notch1 mutations that induce Myc in T-cell acute lymphoblastic leukemia. Blood 128:2229-2240
Basu, Rajatava; Whitley, Sarah K; Bhaumik, Suniti et al. (2015) IL-1 signaling modulates activation of STAT transcription factors to antagonize retinoic acid signaling and control the TH17 cell-iTreg cell balance. Nat Immunol 16:286-95
Stein, Sarah J; Mack, Ethan A; Rome, Kelly S et al. (2015) Tribbles in normal and malignant haematopoiesis. Biochem Soc Trans 43:1112-5
Yashiro-Ohtani, Yumi; Wang, Hongfang; Zang, Chongzhi et al. (2014) Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia. Proc Natl Acad Sci U S A 111:E4946-53

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