Deciphering the HVEM/BTLA pathway’s role in immune-mediated kidney diseases

• Applicant: Dr. Sebastian Brähler
• Subject Area: Nephrology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 420236825

Glomerulonephritides (GN) are a heterogeneous group of inflammatory kidney diseases leading to renal failure by scarring of the filtering units (glomeruli). The molecular mechanisms are poorly understood, which limits our therapeutic options to broad immunosuppression. T cells play key roles in GN, making them attractive therapeutic targets. BTLA (B and T lymphocyte attenuator) is a checkpoint protein that exerts modulatory effects on T cells by binding to the ligand HVEM (herpes virus entry mediator). We have recently demonstrated that BTLA has robust nephroprotective effects in a mouse model of GN. Here, we aim to define the role of HVEM/ BTLA signaling in experimental immune-complex mediated GN and human lupus nephritis. We hypothesize that BTLA on T effector cells is important to receive dampening signals by HVEM. We will therefore first knockout BTLA specifically in CD4 T cells and analyze the impact on experimental GN. As the injection of a BTLA agonistic antibody caused a robust increase of systemic and renal regulatory T cells (Tregs) in our preliminary data, we will next investigate the function of BTLA specifically on Tregs during GN using a Treg-specific knockout mouse line. To understand the effects of BTLA-activity in Th1 and Tregs, we will conduct functional and transcriptomic analyses of both populations after BTLA-stimulation. Secondly, HVEM is the only known ligand for BTLA but also has activating and proinflammatory properties after binding to its ligands LIGHT or CD160. Our Treg functional studies suggest that HVEM might be important for the suppression of T effector cells by Tregs. Therefore, we will analyze the function of HVEM on T-cells in GN in subset-specific knockout mice. In the third aim, we hypothesize that soluble HVEM-Fc can have a dual immunosuppressive effect by activating BTLA and acting as a decoy receptor for pro-inflammatory LIGHT. UL144, a cytomegalovirus (CMV) -ortholog of HVEM, binds and activates BTLA with a high affinity but does not bind LIGHT. We will therefore evaluate the therapeutic potential of enhancing BTLA/HVEM-signaling by injecting HVEM-Fc or UL144-Fc during murine GN. While BTLA has anti-inflammatory and nephroprotective effects in experimental immune-complex mediated GN, it is unclear which patients might benefit from a BTLA/ HVEM-directed therapy. Lupus nephritis is a severe GN in patients with Systemic Lupus Erythematosus (SLE) and recent reports suggest a role of BTLA/ HVEM dysregulation SLE. We will therefore characterize the expression of BTLA, HVEM and CD160 on PBMCs of lupus nephritis patients by CYTOF and analyze kidney biopsies from the same patients by imaging mass cytometry. With these state-of-the-art techniques we will visualize BTLA and HVEM dysregulation during lupus nephritis in the kidney upon diagnosis and longitudinally in circulating immune cells. With this project we hope to make a significant contribution to the precise and effective therapy of GN for our patients .

• DFG Programme: Research Grants