Kidney Week

Abstract: TH-PO530

Immune Checkpoint Molecule B and T Lymphocyte Attenuator and Induces Anti-inflammatory Dendritic Cells in Experimental GN

Session Information

• Glomerular Diseases: Omics, Biomarkers, and Tools
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Trinsch, Bastian, Exzellenzcluster CECAD in der Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany

Bastian Trinsch

• Diefenhardt, Paul, Exzellenzcluster CECAD in der Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany

Paul Diefenhardt, MD

• Nies, Jasper Friedrich, Exzellenzcluster CECAD in der Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany

Jasper Friedrich Nies, MD

• Sierra Gonzalez, Claudio, Exzellenzcluster CECAD in der Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany

Claudio Sierra Gonzalez, MS, MSc

• Koch, Manuel, University of Cologne Center for Molecular Medicine Cologne, Cologne, Nordrhein-Westfalen, Germany

Manuel Koch

• Brinkkoetter, Paul T., Exzellenzcluster CECAD in der Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany

Paul T. Brinkkoetter, MD

• Schermer, Bernhard, Exzellenzcluster CECAD in der Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany

Bernhard Schermer, MD

• Benzing, Thomas, Exzellenzcluster CECAD in der Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany

Thomas Benzing, MD, PhD, FASN

• Braehler, Sebastian, Exzellenzcluster CECAD in der Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany

Sebastian Braehler, MD

Background

T cell-mediated inflammation can lead to crescentic glomerulonephritis (GN). T cell receptor signaling requires secondary signals (immune checkpoints) for T cell activation and differentiation. Interference with this signaling might represent a treatment option for GN. In a recent study, we have shown that the immune checkpoint molecule B and T Lymphocyte Attenuator (BTLA) attenuates inflammation in experimental GN. The complex signaling networks involving different immune cell subsets and the binding partner Herpesvirus entry mediator (HVEM), however, remained unclear.

Methods

Nephrotoxic nephritis (NTN) was induced in mice with a cell-specific knock out of BTLA on T cells or dendritic cells. For treatment studies, HVEM coupled to a human Fc-tag (HVEM-Fc) was produced and administered i.v. in wild-type (wt) mice after NTN induction. Readouts included albuminuria and BUN concentration and histological damage on PAS-stained tissue. Immunophenotyping of kidney tissue and renal lymph nodes was performed using IHC, IF, and flow cytometry. A scRNA-sequencing of renal immune cells was performed in wt and BTLA knock out mice with and without induction of NTN.

Results

Compared to wt, BTLA deficiency on dendritic cells led to a reduction of protective cDC1 in kidney tissue and increased numbers of pro-inflammatory T effector cells. The T cell-specific knock out of BTLA, however, led to a decrease of T regulatory cells (Treg) and to infiltration of monocytes and neutrophils. Both mouse lines showed a dysregulation of T cell polarization in renal lymph nodes. Administration of HVEM-Fc reversed this T cell composition and resulted in increasing numbers of renal cDC1 as well as a decreasing number of renal B cells. ScRNA sequencing confirmed overactivation of T cell subsets and altered survival-associated signaling in cDC1.

Conclusion

The necessity of BTLA for the suppression of T effector cells by Tregs is well-established. Our research now reveals the central importance of BTLA in the immunosuppressive function of cDC1 in glomerulonephritis. The potential of HVEM-Fc, functioning as a BTLA agonist and decoy molecule to inhibit inflammatory LIGHT-signaling, opens up exciting possibilities for future treatment strategies in renal inflammatory diseases.

Funding

• Government Support – Non-U.S.