Under the supervision of Ute Rogner and Amine Toubal, team immunology of diabetes
Obesity is a major public health issue that affects all socio-economic backgrounds. This disease has negatives impact on patients’ everyday life and also has economic repercussions Obesity is associated with numerous co-morbidities including type 2 diabetes and non-alcoholic liver disease (NASH) and is characterized by chronic, low-grade inflammation of the adipose tissue. This inflammation is caused by various cellular mediators of innate and adaptive immunity including pro-inflammatory macrophages, CD8+ lymphocytes, CD4+ Th1 and Th17 lymphocytes.
MAIT cells (Mucosal-Associated Invariant T) are innate like T cells that display features of both innate and adaptative immunity. These unconventional T cells express a semi-invariant TCR and have the ability to respond very rapidly to environmental signals. In the last few years, MAIT cells have been described as deleterious in metabolic and inflammatory diseases such as obesity. Yet, inflammatory molecular mechanisms and the recruitment pathway of MAIT cells in obesity have not been described.
We studied the role of MAIT cells from samples of visceral and subcutaneous adipose tissue, liver and blood, taken during bariatric surgery of obese patients. We characterized the phenotype of MAIT cells in these different tissues and studied their function by measuring the production of several cytokines (TNFα, IFNγ, IL-17 and IL-2) and cytotoxic molecules (Granzyme B). We observed that MAIT cells were more inflammatory in the adipose tissue of obese patients compared to MAIT cells from the blood or liver. Moreover, adipose tissue MAIT cells have a high production of IL-2 that is associated with the decrease of the migration molecule, CCR6, in adipose tissue MAIT cells. This decrease of the CCR6 molecule indicates that MAIT cells could preferentially migrate to the adipose tissue during obesity and remain in this tissue while losing their migratory capacity. To test our migration hypothesis, we used C57BL6/J mouse models on a high fat diet (HFD) or normal diet (ND) that we injected with purified CD45.2 congenic MAIT cells. Less than 24h after the injection of CD45.2 MAIT cells into the mice, we observed their recruitment in the adipose tissue of the HFD mice but not in the ND mice. As obese patients’ MAIT cells are highly exposed to lipids such as fatty acids and oxidized lipids (oxLDL), we studied the impact of this exposition on MAIT cells migratory capacity. We performed in vitro cultures of human MAIT cells with palmitic acid, oleic acid and oxLDL and found that these can impact MAIT cells phenotype and function through the CD36 lipid scavenger receptor as well as the migratory capacity with an increased production of IL-2 and decreased expression of CCR6.
Overall, this thesis describes the involvement of MAIT cells in inflammatory mechanisms during obesity and highlights their migratory capacity and the impact of the lipidic environment on their recruitment into the adipose tissue.
Key words: Obesity, MAIT cells, Adipose tissue, lipids