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DECIPHERING THE ROLE OF TRIB1 IN REGULATORY T CELLS

Periodic Reporting for period 1 - DISTRICT (DECIPHERING THE ROLE OF TRIB1 IN REGULATORY T CELLS)

Reporting period: 2017-07-01 to 2019-06-30

The immune system homeostasis relies on regulatory T cells (Tregs) which are indispensable for peripheral tolerance, notably by preventing the expansion of autoreactive T cells and adjusting the balance between pro and anti-inflammatory signals. Thereby, Tregs are involved in widespread immune-related diseases including autoimmune ones like type-1 or type-2 diabetes and rheumatoid arthritis, and cancers. Additionally, it is known that Tregs play an important role in long-term graft survival in different experimental models and in human kidney transplantation.
Tribbles pseudokinase 1 (TRIB1) is a serine-threonine kinase-like protein with no known catalytic activity which has been described in different pathological settings including cancer or chronic inflammatory diseases such as atherosclerosis and organ transplantation. Previous studies by our group demonstrated the potent value of TRIB1 as a biological marker for chronic antibody-mediated rejection in kidney transplant recipients. TRIB1 participates to various biological functions and is expressed by a large variety of cells suggesting that its function would be environment and tissue dependent. One particularly interesting finding is the over-expression of TRIB1 in Tregs and the high correlation of TRIB1 gene expression with FOXP3 gene and protein expressions suggesting both molecules are co-regulated in Tregs which need further investigation. TRIB1 lack of catalytic domain suggests TRIB1 acts as a scaffold protein, but the role of Trib1 in Tregs remains to be elucidated.
The overall purpose of DISTRICT was to investigate the role of TRIB1 in the Treg biology. The results from this project are the first to highlight the role of TRIB1 in Treg and have implications in immune-related pathologies.
The project relied on the generation of a mouse model of Trib1 Treg-specific deletion obtained during the project. The main step of the DISTRICT project was an exploratory step with complete phenotypic and transcriptomic analyses of mouse Tregs with altered Trib1 expression compared to wild type Tregs. An article describing results from this project are under writing, but overall, we found Trib1 KO mice exhibited signs of immune activation. Further Treg characterization, showed TRIB1 modulates Treg induction, expansion and functions. Thus, TRIB1 absence altered immune system homeostasis. We also highlighted intracellular events driving the expression of TRIB1, showing TRIB1 expression is rapidly induced under the T cell receptor signaling pathway. Preliminary results of this project have presented during the second symposium focused on the biology of the tribbles pseudokinase family which occurred in Beijing (China, May 7th-9th, 2018) and are planned to be submitted to other upcoming meetings.
In addition, we found that TRIB1 gene expression was over-expressed in biopsies from patients with inflamed bowel disease (IBD) compared to controls while previous works found association of TRIB1 single nucleotide polymorphisms with IBD. In our meta-analysis, TRIB1 gene expression was not associated with Treg relative fraction neither anti-TNFα response, certainly due to the presence of many effector cells in IBD. The results of this meta-analysis have been published in 2019 in the Journal of Clinical Investigation where a predictive signature associated with anti-TNFα response for IBD patients has been evidenced (Belarif L. et al. JCI 2019 - free access) and a patent have been created (EP17306039.3).
During this project, outreach activities towards the large public have been done, such as an outreach activity during which renal transplanted patients met researchers (« les chercheurs accueillent les malades » (in 2017) and outreach activities towards high school students in 2018 and 2019 which are visits of the research laboratory with high school students and interventions of researchers in the school in order to explain research activities in an understandable manner ((http://passeportrecherche.univ-nantes.fr/presentation/l-operation-passeport-recherche--530525.kjsp). In 2019, this program ended with a radio program.
By evidencing the role of TRIB1 in Treg biology, these results expand understanding in the molecular mechanisms involved in the biology of Tregs. These results have implications in inflammation and auto-immune disease since Tregs are key-players in immune homeostasis. Furthermore, since a growing interest in Tribbles family protein is observed in the field of cardiovascular disease and cancer, these results will have implication in these fields, particularly in cancer where immunotherapy, notably against Tregs, are used. This project also reinforced or established collaborations within the Tribbles family field.
The publication of an article gathering data obtained throughout this project, under preparation and planned to be submitted by end of 2019, will increase interest for this pleiotropic molecule and foster its usefulness as therapeutic target.
Research efforts during this project also reinforced or established new collaborations to fulfil project needs. This project also improved the fellow’s training, concerning technical aspects and valorization of research and increased his experience in scientific management as an independent researcher.
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