Sirtuins functions in lineages of conventional dendritic cells and IL-35 producing dendritic cell constitutively

• Grant number: 19/07820-0
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Effective date (Start): October 01, 2019
• Effective date (End): March 31, 2020
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Jean de Lima
• Supervisor: Hans Acha-Orbea
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Research place: Université de Lausanne, Épalinges (UNIL), Switzerland
• Associated to the scholarship: 18/04326-1 - The role of sirtuin 1 in the phenotype and function of dendritic cells in the context of organ transplantation in obese animals, BP.MS

Abstract

Histones can model and compact the chromatin in the genome and are present in a number of post-translational processes. Acetylation and deacetylation of histones are two important changes that are provided primarily by histone acetyl transferases (HATs) and histone deacetylases (HDACs), whereby they add and remove, respectively, acetyl groups of specific lysine residues at the histone ends and generate a dynamic level of transcription stabilization. Generally the active genes are associated with acetylated chromatin, whereas transcriptional repression is associated with lower levels or even absence of acetylationSirtuins, also known as class 3 HDAC, have received significant attention since their discovery, which have appeared as a deacetylation component of transcriptional factors. These changes, in turn, influence the cellular metabolism and trigger neurodegenerative, cardiovascular and inflammatory processes.Through phylogenetic analysis it was possible to identify and to divide the sirtuins into four classes: class I (Sirt1, 2 and 3), class II (Sirt4), class III (Sirt5) and class IV (Sirt6 and 7). Sirtuins are found mainly in the nucleus, cytosol and mitochondria of smooth muscle cells, hepatocytes, adipocytes and immune system cells, such as dendritic cells (DC).DCs play a central role in innate and adaptive immunity, in which they act in the production of cytokines in inflammatory and homeostasis contexts, in addition to direct activation of T cells specific for the cognate antigen. As such, DCs play a central role in the immune system.In the context of solid organ transplantation, some DCs subtypes stand out among them, the conventional dendritic cells (cDCs). cDCs are professional antigen-presenting cells resident in the draining lymph nodes. Within the cDCs, it is possible to identify some CD8± CD103 also called cDC1, important for cross-priming CD8 T cells and, to some extent, for the indirect presentation of alloantigens, as well as within the allograft. On the other hand, cDC2, identified as MHC-II CD11c CD11b cells, were initially shown to be derived from specific progenitor and from BMDC, and are dependent on FMS-like tyrosine kinase 3 (Flt3). Functionally, these cells have a high ability to activate CD4 T cells and are equipped with a comprehensive set of TLRs expressing TLRs 5, 6, 7 and 9.When we try to further study the role and how to modulate the functions of certain DCs subpopulations, there are some barriers that still persist, such as the generation and manipulation of specific subtypes in vitro with functional and phenotype characteristic similar to those seen in vivo and in humans. However, The group of Professor Hans Acha-Orbea of University of Lausanne were able to establish DCs lines that constitutively express IL-35, for example, creating conditions to work with cDC1, cDC2 lineages.Therefore, the aim of this project is to verify how Sirt1 can modulate the function and the phenotype of cDC1, cDC2 and IL-35-producing DCs. With this information, we could envisage a function of this HDAC in the context of allogeneic solid organ transplantation. (AU)