Abstract: TH-OR109
CD4 T Cells Promote Cystic Kidney Disease
Session Information
- PKD: Genetic, Mechanistic, and Clinical
October 25, 2018 | Location: 25A, San Diego Convention Center
Abstract Time: 06:06 PM - 06:18 PM
Category: Genetic Diseases of the Kidney
- 1001 Genetic Diseases of the Kidney: Cystic
Authors
- Zimmerman, Kurt, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Song, Cheng 'Jack', Amgen & University of southern california, Los Angeles, California, United States
- Mrug, Michal, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Yoder, Bradley K., University of Alabama at Birmingham, Birmingham, Alabama, United States
Background
The majority of renal cystic diseases are caused by mutations in proteins localized to the primary cilia or proteins required for cilia assembly. Previous data indicate that renal injury markedly accelerates cyst formation and that macrophage numbers are increased prior to and during cyst formation. Depletion of macrophages reduces renal cysts in multiple models of cystic kidney disease. These data led to the hypothesis that cilia and cilia-related proteins regulate innate immune response and cystic disease following renal injury. However, the involvement of adaptive immune cells in renal injury induced cystic disease remains unknown.
Methods
We set out to identify and define the contribution of adaptive immune cells, particularly CD4 T cells, in an ischemia reperfusion injured cilia mutant model of renal cyst formation and in human patients with autosomal dominant polycystic kidney disease (ADPKD).
Results
Our data show that CD4 T cell numbers are increased prior to the formation of renal cysts and are located in regions adjacent to cysts in conditional cilia mutant mice following injury. Further subtyping of CD4 T cells shows that IL-17A producing CD4 T cells (Th17 cells) are increased prior to the formation of renal cysts whereas T regulatory cells (Tregs) are increased during periods of rapid cyst progression. These data suggest that Th17 cells may contribute to the initial stages of cyst formation whereas Tregs may promote cyst expansion. In support of this idea, genetic deletion of adaptive immune cells (RAG1-/- mouse) or pharmacological depletion of CD4 T cells reduced renal cyst formation. These results are complemented by studies in ADPKD patients where we found an increased number of CD4 T cells in regions adjacent to developing cysts. In addition, our preliminary studies revealed the highest serum levels of IL-17A in young ADPKD patients (<30 yrs old) suggesting that, similar to the mouse model, the number of Th17 cells is also highest in early stages of ADPKD. In contrast, PKD patients with ESRD had increased numbers of Tregs, resembling our data obtained in the mouse. Finally, we point to urinary CD4 T cells as a predictor of renal function decline in ADPKD.
Conclusion
Our results suggest that CD4 T cells are an integral component of renal cystic disease and a candidate marker of the disease activity in ADPKD.
Funding
- NIDDK Support