|Sébastien LUCAS||Post-doctoral associate|
|Shirley VALETTE||Research assistant|
|Emilie BERDEAUX||Master student|
Autophagy is a major catabolic pathway in the cells, which constantly delivers cytoplasmic constituents and organelles to the lysosomal compartment for degradation. During this process, a double membrane vesicle the so-called, autophagosome is formed, sequestering (selectively or not), a cytosolic cargo, and then fusing with late endosomes and lysosomes. The formation and function of autophagosomes requires the protein products of 35 autophagy genes (Atgs) some of them are also essential for a non-canonical form of autophagy the so-called LC3-associated phagocytosis (LAP). Both the canonical autophagy pathway, and LAP have been implicated in shaping the innate and adaptive immune responses by acting at multiple and diverse levels such as pathogen clearance, cytokine secretion, and antigen presentation. Therefore, it is not surprising that autophagy pathways have been involved in the initiation and onset of autoimmune and inflammatory diseases.
Our group is focused on studying the contribution of autophagy to antigen presentation pathways in the context of autoimmune and inflammatory disorders. We are interested in how the pathway can impact peripheral tolerance mechanisms, regulatory T cell function and T cell activation.
Analyse the autophagy related MHC class II peptidome in mouse and human antigen presenting cells . We aim to address the contribution of autophagy to the MHC Class II peptide repertoire of auto-antigens, and its potential consequences in peripheral tolerance mechanisms. For this purpose, we analyze the MHC class II ligandome of autophagy deficient mouse and human dendritic cells. In human, we are focusing on selected HLA mono-allelic repertoires such as HLA-DRB1*04:01 that is associated with the pathogenesis of rheumatoid arthritis (RA). In that aspect we study the contribution of autophagy pathways to antigen presentation in synovial fibroblast that are key players in the pathogenesis of RA.
Analyse how autophagy impacts MHC Class 1 expression. We are focused on studying how the pathway regulates the expression of selected HLA class 1 alleles. We have previously shown that autophagy is involved in murine MHC Class 1 degradation and internalization, impacting CD8 T cell responses. The molecular mechanism behind this regulation involves the AAK1 kinase. Our current project aims to determine the role of autophagy pathway in the degradation and recycling of different HLA class 1 alleles, in particular HLA-B*27:05 allele, that is associated with the pathogenesis of ankylosing spondylitis.
Analyse the contribution of autophagy pathways to the dysregulated immune response in mouse models of colitis and arthritis. Using mouse models with conditional deletion of autophagy essential genes in intestinal epithelial cells and antigen presenting cells we aim to address how the pathway contribute to the dysregulated immune response in autoimmune and inflammatory disorders. We have recently shown that autophagy in conventional and unconventional antigen presenting cells (lymphatic endothelial cells) can contribute to regulatory T cell function and homeostasis, and impact the outcome of autoimmune arthritis.