Regulation of systemic lupus via ICOS triggering by mononuclear phagocytes and B cells

• Applicant: Dr. Lino Lars Teichmann
• Subject Area: Rheumatology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 261036931

Systemic lupus erythematosus (SLE) is a relapsing-remitting autoimmune syndrome that leads to multi-organ inflammation and damage. Most frequently women of child-bearing age are affected. Current treatment options for SLE are often not effective or have serious side effects. T cells are key players in the genesis of lupus promoting autoantibody production and directly exerting pathogenic effects. Their activity is controlled by a variety of antigen-presenting cell (APCs) types, such as dendritic cells and macrophages, both of which belong to the mononuclear phagocyte system (MPS), and B cells. We have previously shown that activation of naïve CD4 T cells in lupus-prone MRL.Faslpr mice is entirely dependent on B cells whereas MPS cells are dispensable. However, constitutive deletion of MPS cells greatly impedes T cell expansion and functional differentiation, resulting in substantially less organ inflammation. Specifically which molecular interactions between discrete types of APCs and T cells critically contribute to disease development and what the relevant downstream mechanisms are remains largely unknown. In the proposed study we will therefore investigate to what extent and how triggering of the T cell-expressed co-stimulatory receptor ICOS by its ligand ICOSL on MPS or B cells promotes lupus. For this purpose we have generated MRL.Faslpr mice deficient for the gene Icosl selectively in MPS or B cells. Preliminary results suggest that ICOS ligation by MPS but not B cells drives nephritis. We will expand on these findings and initially evaluate the importance of ICOSL on MPS and B cells for inflammation in multiple lupus target-organs and for the occurrence of various autoantibody specificities and isotypes. Because ICOS stimulates the PI(3)K-Akt signaling pathway we will then test whether ICOS ligation by MPS or B cells is essential for cell cycle progression and survival of activated T cells in lymphoid and peripheral organs. Next, we will analyze whether differentiation of T extrafollicular (TEFH) helper cells (a T cell subset in the splenic red pulp of lupus mice that assists autoantibody formation) and T follicular-like (TFH-like) cells, which we just recently discovered in inflamed peripheral organs of MRL.Faslpr mice, depends on ICOSL on MPS and B cells. Finally, we will examine the hitherto undefined functions of TFH-like cells, their transcriptional relatedness to TEFH cells and the ubiquity of their involvement in autoimmune inflammation. These studies are important because they uncover the requirements for T cell-mediated inflammation and new ways to intervene therapeutically.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Joachim L. Schultze