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ESR Project 2: Trib1-mediated control of Treg function and its role in maintaining adipose tissue health.

yodit

Yodit Feseha

Obesity is currently considered a global epidemic. Obesity increases the prevalence of common diseases such as type 2 diabetes, cardiovascular diseases, and several cancers. This has increased mortality and morbidity rate, also placing a financial strain on the health care system. Excess energy is stored in adipose tissue (AT). AT is an endocrine organ, consists of adipocytes and the stromal-vascular fraction (fibroblasts, preadipocytes, endothelial, and immune cells). Adipocytes secrete adipokines, cytokines, and chemokines involved in a build-up of pro-inflammatory immune cells (Grant R.W. & Dixit V.P. 2015). While pro-inflammatory immune cells such as CD4+ Th1, CD8+ T cells and M1 macrophages accumulate in obese adipose tissue, anti-inflammatory cells including CD4+ regulatory T lymphocytes (Treg) are decreased (Feuerer M. et al., Nat. Med 2009).

 

Treg are key players in immune system homeostasis. They prevent autoimmune diseases by establishing and maintain immunologic self-tolerance (Sakaguchi S. et al., 2008). Thereby, Treg are involved in widespread immune-related diseases including autoimmune ones like type-1 or type-2 diabetes and rheumatoid arthritis, and cancers. Various immunotherapy strategies are proposed boosting Treg to cure or to prevent auto-immune disorders including type 2 diabetes or colitis or depleting Treg to improve vaccination against infectious diseases or increase anti-tumoral immune response (Hippen K. et al., 2011).

Adipocyte resident “fat Treg” may account for 50 to 70% of CD4+ T cells. In obese conditions, Treg cells depletion increases insulin resistance and local system production of pro-inflammatory cytokines and conversely, in vivo Treg expansion can reverse such insulin resistance (Feuerer M. et al, Nat. Med 2009; Vasanthakumar A. et al., 2015). Further elucidation of the role of Treg cells in the development of metabolic dysfunction is thus required.

 

Interestingly, our research team has previous identified Tribbles pseudokinase 1 (TRIB1) to play a role in Treg biology. TRIB1 is a serine-threonine pseudokinase protein. Located on chromosome 8, TRIB1 contains an N-terminal domain, pseudokinase domain, and a C-terminal domain. Kinase-like domain loop in the pseudokinase domain is highly conserved which indicated its importance in the role of TRIB1. Functional roles of this molecule remain to be elucidated but its lack of catalytic domain, its intracellular location, cytoplasmic and nuclear, suggests TRIB1 acts as a scaffold protein.

screen-shot-2017-05-10-at-15-56-14

Figure1: Structure of TRIB1 protein (Johnston J & Kiss-Toth E. 2015)

 

While TRIB1 is over-expressed in Treg (Dugast E. et al., 2013; Ferraro A. et al., 2014), TRIB1 directly interacts with FOXP3, a master transcription factor of regulatory T cells. In vitro, an overexpression of TRIB1 in CD4+ T lymphocytes reduces their proliferation capacity (Dugast E. et al., 2013). These studies indicate TRIB1 to play a role in the Treg biology and our current hypothesis is that by interacting with FOXP3, TRIB1 participates to the multiprotein regulatory complex driven by FOXP3 (Li B. et al., 2007) and modulates the downstream transcriptional program which is essential for Treg homeostasis, stability, proliferation and function (illustrated in figure 2).

Figure 2: overall working hypothesis for Trib1 role in Treg.screen-shot-2017-05-10-at-15-56-34

 

As a scaffold protein, TRIB1 participates to the supramolecular regulatory complex driven by FOXP3 (Li B. et al., 2007).

In addition, GWAS studies identified SNP close to TRIB1 locus in significant association with dysregulated cholesterol levels, high-density lipoproteins, and triglyceride levels (Burkhardt et al. 2010, Douvris et al. 2014).

While several studies have connected TRIB1 to dysfunction of Treg cells and metabolic disorders; the underpinning molecular mechanism of TRIB1 needs examination.

 

Research Objective

In the duration of the PhD, I will be looking into the functional roles of TRIB1 in Treg from adipose tissue with 2 main objectives:

  1. The impact of Treg-specific knockout of TRIB1 in the development of obesity and its effect on AT resident cells.
  2. The understanding of TRIB1 role in intracellular events in fat Treg.

Reference

Burkhardt R., S. A. Toh, W. R. Lagor, et al. (2010). “Trib1 is a lipid- and myocardial infarction-associated gene that regulates hepatic lipogenesis and VLDL production in mice.” J Clin Invest 120(12): 4410-4414.

Douvris A., S. Soubeyrand, T. Naing, et al. (2014). “Functional analysis of the TRIB1 associated locus linked to plasma triglycerides and coronary artery disease.” J Am Heart Assoc 3(3): e000884.

Dugast E., E. Kiss-Toth, J. P. Soulillou, et al. (2013). “The Tribbles-1 protein in humans: roles and functions in health and disease.” Curr Mol Med 13(1): 80-85.

Dugast E., E. Kiss-Toth, L. Docherty, et al. (2013). “Identification of tribbles-1 as a novel binding partner of Foxp3 in regulatory T cells.” J Biol Chem 288(14): 10051-10060.

Ferraro, A., A. M. D’Alise, T. Raj, et al. (2014). “Interindividual variation in human T regulatory cells.” Proc Natl Acad Sci U S A 111(12): E1111-1120.

Feuerer M, L Herrero, D Cipolletta, et al., (2009) “Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters.” Nat Med 15(8): 930-9.

Grant R., & V.P. Dixit, (2015) “Adipose tissue as an immunological organ.” Obesity 23(3): 512-518.

Hippen, K. L., J. L. Riley, C. H. June, et al. (2011). “Clinical perspectives for regulatory T cells in transplantation tolerance.” Semin Immunol 23(6): 462-468.

Johnston J. & Kiss-Toth E. (2015) “TRIB1 (Tribbles Pseudokinase 1).” Atlas Genet Cytogenet Oncol Haematol. In press.

Li, B., A. Samanta X. Song, et al. (2007). “FOXP3 is a homo-oligomer and a component of a supramolecular regulatory complex disabled in the human XLAAD/IPEX autoimmune disease.” Int Immunol 19(7): 825-835.

Sakaguchi, S., T. Yamaguchi, T. Nomura, et al. (2008). “Regulatory T cells and immune tolerance.” Cell 133(5): 775-787.

Vasanthakumar, A., K. Moro, A. Xin, et al. (2015). “The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells.” Nat Immunol 16(3): 276-285.