Séminaire CIRI : Dr Ghita GHISLAT
Date / Heure
Date(s) - 24/11/2020
11 h 00 min - 12 h 15 min
Dr. Ghita GHISLAT (Centre d’Immunologie Marseille Luminy); « Crosstalk between NF-kB and autophagy in dentritic cells during inflammation ».
The efficiency of immune defence strategies against a plethora of infectious challenges and cancer relies on a balance between anti- and pro-inflammatory responses. These divergent immune responses are orchestrated by dendritic cells (DC) that sense endogenous innocuous antigens or exogenous insults through enduring tolerogenic or immunogenic maturation, respectively. Thus, fine-tuning of the mechanisms that drive these DC opposing maturation states represent tailorable therapeutic opportunities to overcome antimicrobial and immunotherapy resistances. However, the signalling cascades that shape the intracellular activities of DC are still largely unexplored, mostly because of their heterogeneity. Classical DC can be subdivided into two main subsets specialised in different functions: conventional DC type 1 (cDC1) and type 2 (cDC2). Although this classification remains simplistic, the current view holds that cDC1 initiate CD8+ T cell responses while cDC2 activate CD4+ T cells.
We explored at single cell resolution the molecular determinants of the cDC1 immunogenic maturation by performing scRNAseq analysis on cDC1 infiltrated in immunogenic tumours. We found that NF-kB coordinates a dynamic maturation of tumour-associated cDC1. Transgenic mice lacking active NF-kB exclusively in cDC1 bearing melanoma showed that this transcription factor governs the ability of cDC1 to recruit and activate cytotoxic lymphocytes to tumours, leading to the immune control of cancer. Furthermore, analysis of clinical data from The Cancer Genome Atlas revealed that NF-κB in cDC1 outlines the frequency of activated CD8+ T cells in human melanoma and triple negative breast cancer, and improves the disease prognosis.
An important intracellular process that shares with NF-κB the property of being auto-protective for the organism is autophagy. Preliminary results lend to an inception of deciphering the interplay between autophagy and NF-κB in tolerogenic DC that could be relevant for the autophagy-related pathogenesis Crohn’s disease. Dissecting these mechanisms will ultimately open the possibility to modulate the function of the appropriate DC subset for Crohn’s disease therapy