Focus
- Cell biological and metabolic control of TLR activation and MHC class I cross-presentation
- Regulation of beta cell-directed autoimmunity by antimicrobial peptides and the intrinsic beta cell reponse
Introduction
Protective anti-pathogen as well as unwanted anti-self immunity implicates sequential activation of innate and adaptive responses. The discovery of intracellular antigen processing machineries starting in the early 90s revealed how ligands recognized in adaptive T cell reponses are produced, although the underlying cell biology, notably concerning (cross-)presentation of exogenous ligands, remains incompletely understood. More recently the focus has shifted to the innate response, preceding and controling the adaptive response. Because activation of the innate response is tightly linked to intracellular receptor trafficking, studying the cell biology of antigen presenting cells is primordial for its understanding. A prime example is the activation of Toll-like receptors (TLRs) in endocytic compartments which in turn modulates cross-presentation, illustrating the intimate connection between innate and adaptive responses. Exciting very recent results including data obtained by us suggest that innate signaling is also affected by the cellular and notably energetic metabolism, which for example by modifying the lipid composition of endocytic membranes controls TLR activation.
While in part specific innate and antigen processing pathways are involved in autoimmune type 1 diabetes (T1D), recent results, including some obtained by our team, indicate a role for beta cell intrinsic mechanisms modulating the course of the autoimmune aggression, as well as for cross-talk between beta cells and the intestinal microbiota. However, the mechanisms underlying both pathways remain largely unexplored.
Research objectives
- To understand how trafficking in the endocytic pathway regulates TLR activation as well as cross-presentation
- To elucidate endocytic trafficking pathways underlying efficient cross-presentation by splenic CD169 macrophages and study the contrbution of these cells to generation of T cell immunity
- To decipher the cell biological alterations, especially in the endolysosomal system, resulting from gene mutations in patients with severe metabolic diseases and to understand how they trigger innate inflammatory pathways
- To study a novel pathway boosted in the absence of insulin-degrading enzyme (IDE) mediating beta cell regeneration and protection from autoimmunity
- To study the role of the innate immune system in autoimmune diseases, with a focus on the immunoregulatory potential of anti-microbial peptides and the gut microbiota in type 1 diabetes and in multiple sclerosis
5 main publications
- Enée E et al.
ZnT8 is a major CD8+ T cell-recognized autoantigen in pediatric type 1 diabetes.
Diabetes 61 (2012): 1779-84
- Miani M, Le Naour J, Waeckel-Énée É, Verma SC, Straube M, van Endert P, Sokol H, Diana J.
Interplay between the gut microbiota and innate lymphoid cells stimulates ß-defensin 14 expression by pancreatic endocrine cells regulating autoimmune diabetes.
Cell Metab. (2018) pii: S1550-4131(18)30394-2. doi: 10.1016/j.cmet.2018.06.012
- Diana J et al.
Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes.
Nat. Med. 19 (2013): 65-73
- Sun J et al.
Pancreatic beta cells express a cathelicidin-related antimicrobial peptide regulating autoimmune diabetes.
Immunity 43 (2015): 304-17
- Van Endert P.
Intracellular recycling and cross-presentation by MHC class I molecules.
Immunol. Rev. 272 (2016): 80-96
