Migration pattern of MAIT cells between blood circulation and omental adipose tissue associated with changes in intestinal microbiota in the inflammatory context of obesity associated with type 2 diabetes mellitus

• Grant number: 24/10027-8
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2024
• End date: November 30, 2025
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Lucas Ferreira Mendanha
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 23/07482-2 - Sensing extra and intracellular stressors by renal and immune cells: new insights into signal reception and transduction, and their relevance for understanding renal diseases, AP.TEM

Abstract

MAIT cells are T lymphocytes V±7.2+CD161hiMR1+CD4-CD3+ that present semi-invariant chains in the TCR receptors and were initially described in mucosal regions. From this description, they were termed Mucosal-Associated Invariant T cells (MAIT cells). In these regions, under homeostatic conditions, they respond to metabolites from the riboflavin biosynthesis pathway (5-OP-RU) produced by commensal flora, promoting the reinforcement of tight junctions, mucin production, and tissue repair, ensuring the integrity of the epithelial barrier. However, under pathological conditions such as alterations in the microbiota and pathological increase in intestinal epithelial barrier permeability, these cells activate, in response, a phenotype that orchestrates the inflammatory process by activating and regulating other cells present, such as macrophages and B lymphocytes, aiming to restore homeostasis in the region. It has been demonstrated that MAIT cell activation occurs via two pathways: TCR-dependent, with presentation of the compound 5-OP-RU by MR1 complexes on APCs, and TCR-independent, through the interaction of interleukins produced in the inflammatory context. It has also been shown that these cells are present in other regions of the human body such as the skin, lungs, liver, bloodstream, and adipose tissue, suggesting that they may have functions beyond mucosal homeostasis maintenance, playing a relevant role in other situations. In the context of obesity associated with type 2 Diabetes Mellitus, it has been observed that there is a significant alteration in the frequencies of MAIT cells in the bloodstream, where there is a significant decrease, and in the omental adipose tissue, where there is a considerable increase. It is noted that the causes of this change have not yet been fully described, leaving ample space for the elucidation of the mechanisms by which they occur. This study aims to contribute to this discussion by addressing the view that these frequency changes result from an active process of migration of MAIT cells to the inflamed omental adipose tissue. This process would be greatly increased due to the fact that MAIT cells in the bloodstream may be hyperactivated in the face of high presentation of 5-OP-RU by APCs, since the integrity of the intestinal epithelial barrier, like the microbiota, is altered, allowing the diffusion of such activating molecules. This activation pattern, along with the significant release of chemokines by the inflamed adipose tissue, would favor the migration of these cells to the region in question, justifying the experimental data found in previous studies. Thus, we will investigate the presence of 5-OP-RU in the bloodstream of mice with induced obesity and T2DM with alterations in the intestinal microbiota. Subsequently, we will analyze the increase in markers of cell activation, migration and production of proteins characteristic of this process in MAIT cells in the bloodstream using Flow Cytometry and PCR. Later, we will analyze the presence of activated MAIT cells in the omental adipose tissue that present a pattern of cellular receptors consistent with those of bloodstream cells or that present cellular receptors in an intermediate pattern between that of bloodstream and natural tissue cells, also using flow cytometry.