Chronic inflammatory diseases (IDs) are the third cause of death in developed countries, after cancer and cardiovascular disorders, and their prevalence is growing in westernized countries. These diseases constitute a heterogeneous group of illnesses, including non-exhaustively, rheumatic diseases (rheumatoid arthritis (RA)), autoimmune systemic diseases (systemic lupus erythematosus (SLE)), and inflammatory bowel disorders (IBDs). All these diseases, which appear clinically different, share many similarities, such as common genetic background, common pathophysiological pathways and not surprisingly similar treatments. They are characterized by an autoimmune response with circulating autoantibodies secreted by B cells, which are activated by a specific subset of effector CD4+ T cells, follicular helper T cells (Tfh). Tissue lesions in these pathologies involve another subset of effector T cell, the IL17-secreting T cells (Th17). Interestingly, we recently highlighted the crucial role of CD95L in SLE pathogenesis. CD95L (FasL) belongs to the TNF family. While its receptor CD95 (Fas) is ubiquitously expressed, CD95L is mainly detected at the surface of lymphocytes and NK cells where it plays a pivotal role in the elimination of infected and transformed cells. CD95L is a transmembrane protein acting through cell-to-cell contact but it can be cleaved by metalloproteases, releasing a soluble ligand (cleaved CD95L or cl-CD95L) whose biological function remains to be defined. We observed that cl-CD95L is increased in lupus patients, and this soluble ligand aggravates inflammation in SLE by inducing non-apoptotic signaling pathways (NF-?B and PI3K). CD95 harbors an intracellular stretch designated death domain (DD). Binding of membrane-bound CD95L to CD95 leads to the recruitment of the adaptor protein FADD via the DD. FADD in turn aggregates the initiator caspase-8 and caspase-10. The CD95/FADD/caspase complex is called death-inducing signalling complex (DISC) and implements the apoptotic signaling pathway. In contrast, cl-CD95L fails to form DISC, but instead triggers the formation of a non-apoptotic complex termed motility-inducing signaling complex (MISC) inducing a Ca2+ response. Recent data from our group highlighted that this Ca2+ response occurred through the direct recruitment of PLC?1 by CD95. Indeed, in presence of cl-CD95L, the juxtamembrane region of CD95, called calcium-inducing domain (CID), binds PLC?1 to induce endothelial transmigration of Th17 cells in SLE (Immunity, 2017). Moreover, a chimeric molecule consisting of the CID conjugated to the cell-penetrating domain (designated TAT-CID) binds PLC?1 and prevents its recruitment to CD95. Strikingly, injections of TAT-CID in lupus-prone mice dampen the accumulation of Th17 cells in inflamed organs and alleviate clinical symptoms. Our preliminary data indicate that cl-CD95L also triggers endothelial transmigration of Tfh cells and this process is inhibited by TAT-CID. Furthermore, cl-CD95L favors the activation of Tfh cells and by doing so, their ability to promote the differentiation of B cells into Ig-producing plasma cells. These data urge us to investigate the molecular mechanisms by which cl-CD95L stimulates Tfh cells and decipher whether the therapeutic effect of TAT-CID in lupus-prone mice is related to a combined action on Th17 and Tfh cells. Our consortium intends to address whether i) cl-CD95L is increased not only in the sera of SLE patients but also in those of RA and IBD patients and ii) how this ligand promotes migration/differentiation in Th17 and Tfh cells. Also, using Protein-fragment complementation assay (PCA), high-throughput screening will be performed iii) to identify new inhibitors of CD95/PLC?1 interaction. In conclusion, this project will extend our observations on the role of cl-CD95L in several Th17 and/or Tfh-driven IDs and translate those results into innovative therapeutic molecules for ID patients.