Analysis of the SLAM-SAP signaling pathway in the mechanisms regulating inflammation through IL-17 production: implication of iNKT and conventional T cells. – iNKT-SAP

This proposal aims at a better understanding of the cellular and molecular mechanisms of inflammatory responses involving iNKT cells and SLAM-R/SAP signaling pathways.

Inflammation is a complex process mediated by both innate and acquired immune responses and is essential to protect the host from harmful stimuli such as pathogens, damaged cells or irritants. However, when uncontrolled it becomes pathological. For this reason, inflammation is normally closely regulated by the cross-talk between innate and acquired immune responses. Among the regulatory T cell populations and factors influencing this process we can mention invariant Natural Killer T (iNKT) cells, IL-17 and the SLAM (signaling lymphocytic activation molecule) family receptors (SLAM-R) and SAP (SLAM-associated protein) dependent pathways. The latter play a pivotal role in the control of several immune responses implicating T, B and NK cells. Moreover, SAP is critically needed for the development of iNKT cells. These cells represent a particular lineage of T lymphocytes capable to promptly and massively produce Th1, Th2 and Th17 cytokines such as IFN-?, IL-4 and IL-17. By these means, they bridge innate and acquired immunity and regulate the outcome of numerous inflammatory immune responses. Consequently, these cells are considered as a “swiss-army knife” of the immune system and should be tightly controlled. In this context, it was already reported that SAP is critically needed for the development of iNKT cells and our recent findings demonstrate that SAP signaling can also regulate the IL-17-producing capacities of these cells. Since this cytokine plays a pivotal role in inflammation, we could hypothesize that SLAM-R/SAP signaling pathways can influence inflammatory responses by controlling IL-17 production.

In the present project, we propose to dissect this new mechanism capable to influence inflammatory responses. For this, we will perform in vitro assays to determine the molecular mechanisms implicated, use experimental mice models of lung inflammation, and finally analyze human cells from health donors and from SAP-deficient patients. Results obtained will highlight potentially new mechanisms influencing the pathophysiology of some inflammatory diseases and propose new therapeutic trials.

This project cannot be achieved without the expertise of the three teams who accepted to join forces to take up this challenge:

Partner 1 (coord): Maria Leite-de-Moraes et collaborateurs, CNRS UMR8147, Hôpital Necker, Paris
Partner 2: Sylvain Latour et collaborateurs, INSERM 768, Hôpital Necker, Paris
Partner 3: Gérard Eberl et collaborateurs, Institut Pasteur, Paris.