Kidney Week

Abstract: SA-PO088

Unraveling Autoimmunity and Tissue Residency in a Model of CD8 T Cell-Driven Nephritis

Session Information

• AKI: Inflammation and Cell Cycle
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Arnold, Frederic, Department of Internal Medicine IV, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg, Germany

Frederic Arnold, MD

• Kupferschmid, Laurence, Institute for Microbiology and Hygiene, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg, Germany

Laurence Kupferschmid

• Weissenborn, Philipp, Institute for Microbiology and Hygiene, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg, Germany

Philipp Weissenborn

• -, Sagar, Department of Internal Medicine II, University Medical Center Freiburg, Freiburg, Germany

Sagar -, PhD

• Rogg, Manuel, Institute for Pathology, University Medical Center Freiburg, Freiburg, Germany

Manuel Rogg

• Schell, Christoph, Institute for Pathology, University Medical Center Freiburg, Freiburg, Germany

Christoph Schell, MD, PhD

• Tanriver, Yakup, Department of Internal Medicine IV, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg, Germany

Yakup Tanriver, MD

Group or Team Name

• AG Tanriver.

Background

There is strong evidence, that autoreactive cytotoxic T cells (CTLs) play a crucial role in different forms of autoimmune nephritis (e.g., acute interstitial nephritis or immune checkpoint inhibitor-related nephritis). Yet, mechanisms of differentiation and memory formation of autoreactive CTLs in the kidney are poorly understood. Distinct tissue-resident memory T cells (T_RM) providing localized immunity have been identified in the kidney. However, their role in context of renal autoimmunity remains elusive.

Methods

A murine model of CTL-driven nephritis was established to dissect the role of autoreactive CTLs. It is based on NOH mice, that express ovalbumin (OVA) on podocytes. CTL-driven autoreactivity was induced by adoptive transfer of OVA-specific CTLs (OT-1 cells) into NOH hosts and activation through infection with OVA-expressing pathogens. The transcriptome and T cell phenotype was analyzed applying scRNASeq and multi-dimensinal flow cytometry on circulating and renal CTLs. Additional histopathological analysis was performed on kidneys of NOH mice and patients with interstitial nephritis.

Results

Autoreactive CTLs induced a robust renal phenotype in NOH mice. Despite the phenotype, peripheral OT-1 counts declined more rapidly in NOH vs. wildtype mice. In line with that, scRNASeq and cytometry analysis of OT-1 cells revealed a distinct peripheral T memory phenotype. It was characterized by higher expression of markers associated with T cell dysfunction (e.g., Tox, Ctla4, Lag3), indicating functional restriction of autoreactive CTLs. While peripheral immunity appeared curtailed, robust accumulation of OT-1 cells was detected in kidneys of NOH mice. Within OT-1 infiltrates a subpopulation of autoreactive renal T_RM cells (CD103⁺CD69⁺), most likely required for maintaining the phenotype, could be identified. Histopathological analysis of human samples revealed a comparable T_RM subpopulation in interstitial nephritis.

Conclusion

CTLs show a distinct transcriptome and immune phenotype in a model of CTL-driven nephritis. While the systemic immune response is curtailed, CTLs persistently accumulate at the site of autoantigen cross-presentation. Differentiation of T_RM cells within infiltrates of mice and nephritis patients indicate a crucial role of renal T_RM cells in context of sustained renal autoimmunity.

Funding

• Government Support – Non-U.S.