STress response and Immunity Modulation – STIM

STress response and Immunity Modulation (STIM) is an exploratory research project at the interface of cell biology, genomics and immunology, aiming at unraveling how the Integrated Stress Response (ISR), contributes to the regulation of immunity and potentially to auto-immunity onset. The ISR is essential for the differentiation and function of plasmacytoïd dendritic cells (pDCs) and B cells, two main cellular contributors to the auto-immune process, and growing evidence indicate that immune responses can be adversely affected by abnormalities in this biochemical pathway. Different cellular stress and insults induce the ISR, that consist in an important reduction of protein synthesis triggered by different kinases of the EIF2AK family, like EIF2AK3/PERK, while establishing a transcriptional program to favor stress resolution and cell survival. The existence of pediatric patients susceptible to familial interferonopathies and displaying mutations in the Eif2ak3/Perk gene, underlines the importance of the ISR in the auto-immune process, and reinforces the relevance of this project for human health. These mutations could favor autoimmunity by creating biochemical conditions favoring type-I IFN expression and potentially interferonopathies prone physiological landscapes in patients. With our multidisciplinary approach (including scRNAseq, ribosome profiling and proteomics), we will establish how the synergy between microbial sensing and the ISR contributes to pDC and B cell activation, explain the autoimmune conditions of the patient families bearing mutations in eif2ak genes, and potentially open a new path towards therapeutic solutions to reduce autoimmune manifestations.

This research program based on an extensive array of preliminary data will aim at achieving the following aims:
1: Defining the role of the ISR in pDC and B cell function in vitro and in vivo by exploring global alterations in their cell biology in resting and inflammatory conditions.
2: Characterizing mRNAs differentially expressed and impacting key immune function in cells deleted in ISR genes or in PBMC isolated from auto-immune patients.
3: Bringing the proof of concept that harnessing pharmacologically the ISR could regulate auto-immunity.