Kidney Week

Abstract: TH-OR108

CD8+ T-Cells Regulate Progression of Autosomal Dominant Polycystic Kidney Disease

Session Information

• PKD: Genetic, Mechanistic, and Clinical
  October 25, 2018 | Location: 25A, San Diego Convention Center
  Abstract Time: 05:54 PM - 06:06 PM

Category: Genetic Diseases of the Kidney

• 1001 Genetic Diseases of the Kidney: Cystic

Authors

• Tyler, Logan C., University of Colorado Denver, AMC, Aurora, Colorado, United States

Logan C. Tyler

• Kleczko, Emily K., University of Colorado Denver, AMC, Aurora, Colorado, United States

Emily K. Kleczko,

• Marsh, Kenneth H., University of Colorado Denver, AMC, Aurora, Colorado, United States

Kenneth H. Marsh,

• Wallace, Darren P., University of Kansas Medical Center, Kansas City, Kansas, United States

Darren P. Wallace,

• Chonchol, Michel, University of Colorado Denver, AMC, Aurora, Colorado, United States

Michel Chonchol,

• Gitomer, Berenice Y., University of Colorado Denver, AMC, Aurora, Colorado, United States

Berenice Y. Gitomer,

• Nemenoff, Raphael A., University of Colorado Denver, AMC, Aurora, Colorado, United States

Raphael A. Nemenoff,

• Hopp, Katharina, University of Colorado Denver, AMC, Aurora, Colorado, United States

Katharina Hopp,

Background

Therapeutic strategies to treat Autosomal Dominant Polycystic Kidney Disease (ADPKD) have largely focused on targeting abnormal renal epithelial cell signaling. In cancer, a disease with many parallels to ADPKD, modulating the activity of cells within the microenvironment, specifically CD8⁺ T-cells, has shown remarkable therapeutic effects. However, the role of CD8⁺ T-cells and their potential as a novel therapeutic target in ADPKD has not been well studied.

Methods

Using the murine ADPKD model Pkd1 p.R3277C [RC], as well as stored human ADPKD/Autosomal Recessive PKD (ARPKD) kidney tissue, we explored the role of renal CD8⁺ T-cells via flow cytometry, in situ/immunofluorescence (IF) imaging, qPCR, and pharmacological intervention.

Results

Using flow cytometry and IF, we previously showed that CD8⁺ T-cells increase in numbers, become selectively activated, and localize to cystic regions in Pkd1^RC/RC vs. wildtype (WT) kidneys. Further, CD8⁺ T-cell depletion worsened PKD pathology in Pkd1^RC/RC mice. By in situ hybridization we now show that Pkd1^RC/RC interstitial and cystic epithelial cells express higher levels of CD8⁺ T-cell recruiting chemokines (Cxcl9/Cxcl10) vs. WT, implying active recruitment of CD8⁺ T-cells to cystic lesions. We confirmed these findings in human ADPKD/ARPKD vs. healthy control kidneys and demonstrated in vitro that human PKD1^-/- renal epithelial cells have higher basal CXCL9/10 levels, as well as a greater increase in response to IFNg vs. PKD1^+/+ cells. To understand how CD8⁺ T-cells may halt cyst progression, we performed TUNEL and PCNA staining in Pkd1^RC/RC anti-IgG and anti-CD8 treated animals. Mice depleted of CD8⁺ T-cells had fewer apoptotic and more proliferating cystic epithelial cells vs. control, consistent with CD8⁺ T-cell-mediated cytotoxicity and IFNg-induced reduction in proliferation.

Conclusion

These data indicate that CD8⁺ T-cells are recruited specifically to cystic lesions via chemokine production by interstitial and cystic epithelial cells and halt ADPKD progression through modulating cyst expansion via apoptosis/proliferation. Hence, therapeutic strategies aimed at increasing CD8⁺ T-cell numbers/activity may represent novel treatment approaches to slow ADPKD progression.