Loading
Tissue-resident memory cells (Trm) are a subset of memory T cells that stably reside in non-lymphoid tissues, where they provide immediate protection against pathogen infection. Trm have also been shown to sustain inflammation in various chronic and autoimmune conditions. Indeed, our recent published study demonstrated that the development of autoreactive Trm could be an important mechanism in the chronic course of central nervous system (CNS) autoimmune diseases such as multiple sclerosis and paraneoplasic neurological disorders. Although some cues driving CD8 Trm differentiation and/or maintenance have been recently described the exact pathways mobilised to promote their long-term persistence in the CNS remain unknown. To gain a better insight into the molecular mechanisms underpinning Trm persistence during chronic CNS pathologies, we made use of a model of latent infection with the Toxoplasma gondii parasite and a mouse model of neuroral autoimmunity mediated by autoreactive CD8 T cells. Our single-cell RNA-seq analyses of brain CD8 Trm cells showed that specific prosurvival molecules from the Bcl2-protein family and the IFNgR1 signalling pathway were induced in Trm cells compared to their recirculating counterparts. Our preliminary data suggested that the inhibition of these molecules/pathways in CD8 T cells using shRNA and/or Crispr-cas9 technology led to a strong defect in Trm maintenance in the brain. Based on these preliminary findings, we postulate that brain Trm rely on specific prosurvival molecules from the mitochondrial apoptotic pathway and on the IFNgR1-signalling pathway for their long-term maintenance within the CNS. We are now aiming to (i) determine the phenotypic and the physiopathological consequences of the inhibition of pro-survival molecules of the Bcl2 family in Trm during autoimmunity and persistent pathogen infection of the CNS, (ii) elucidate the molecular mechanisms underpinning the IFNgR1-signalling mediated persistence of brain Trm in these two models of CNS inflammation, and (iii) validate in human brain Trm the relevance of these pathways using tissue samples from patients with infectious or autoimmune CNS diseases. Overall, this project will provide a better understanding of the mechanisms underpinning the survival/retention of Trm within the CNS. Therefore, it represents an important step for the design of new therapies against chronic neuroinflammatory diseases, which would aim to modulate Trm density in the CNS, either to promote their potential beneficial persistence during a chronic pathogen infection, or conversely to decrease their survival in order to reduce chronic inflammation.
<script type="text/javascript">
<!--
document.write('<div id="oa_widget"></div>');
document.write('<script type="text/javascript" src="https://www.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=anr_________::ce30b756c2afd14813123390d95e66a1&type=result"></script>');
-->
</script>