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PhD Thesis - Mrs Tamara Sneperger

Tamara Sneperger

Identification of the LRP1 receptor as an endogenous ligand for the dendritic cell immunoreceptor DCIR

PhD thesis committee

  • Prof. Boucher Philippe, Laboratoire de Bioimagerie et Pathologies, Strasbourg - Referee
  • Dr. Lena Alexopoulou, Centre d’Immunologie de Marseille-Luminy, Marseille - Referee
  • Dr. Sylvain Perruche, EFS Bourgogne Franche Comté, Besançon - Referee 
  • Prof. Joost Van Meerwijk, Institut Toulousain des Maladies Infectieuses et Inflammatoires, Toulouse - Examiner
  • Dr. Olivier Neyrolles, Institut de Pharmacologie et de Biologie Structurale, Toulouse – PhD co-supervisor
  • Dr. Yoann Rombouts, Institut de Pharmacologie et de Biologie Structurale, Toulouse – PhD supervisor

Abstract

Tuberculosis (TB) is an immunopathology caused by Mycobacterium tuberculosis (Mtb) and remains one of the top ten causes of death worldwide (WHO’s Global Tuberculosis Report 2022). Therefore, there is an urgent need to improve our understanding of anti-TB immunity in order to develop innovative therapies. We recently discovered that the dendritic cell immunoreceptor (DCIR) negatively modulates anti-TB immunity. In particular, the absence of DCIR in mice results in an improved adaptive immune-mediated pulmonary clearance of Mtb. However, the absence of a known ligand for DCIR greatly hindered our understanding of the exact functions of this receptor in immunity. To address this issue, we used a combination of biochemical and immunological approaches to identify the first endogenous ligand for DCIR: the low-density lipoprotein receptor-related protein 1 (LRP1). In addition to carrying LRP1 at their cell surface, myeloid cells strongly express DCIR itself, with macrophages and dendritic cells (DCs) being the cells expressing the most DCIR and LRP1. Using confocal microscopy experiments and proximity ligation assays, we found that DCIR colocalizes with LRP1 at the surface of mouse and human macrophages / DCs, supporting the concept of a cis interaction (on the surface of the same cell) between DCIR and LRP1. Of note, DCIR may also interact with LRP1 in trans between cells in close proximity. Importantly, we also showed that DCIR regulates a major LRP1 function namely endocytosis. Collectively, our data provide fundamental insights into the understanding of the role of DCIR in anti-TB immunity and may offer new avenues for the development of host-directed therapy, targeting the DCIR/LRP1 axis, to treat TB.

23 Mar

09:30 - 13:30

Fernand Gallais Conference room