PD-L1 (Programmed Death Ligand 1) Regulates T-Cell Differentiation to Control Adaptive Venous Remodeling

Arterioscler Thromb Vasc Biol. 2021 Dec;41(12):2909-2922. doi: 10.1161/ATVBAHA.121.316380. Epub 2021 Oct 21.

Abstract

Objective: Patients with end-stage renal disease depend on hemodialysis for survival. Although arteriovenous fistulae (AVF) are the preferred vascular access for hemodialysis, the primary success rate of AVF is only 30% to 50% within 6 months, showing an urgent need for improvement. PD-L1 (programmed death ligand 1) is a ligand that regulates T-cell activity. Since T cells have an important role during AVF maturation, we hypothesized that PD-L1 regulates T cells to control venous remodeling that occurs during AVF maturation. Approach and results: In the mouse aortocaval fistula model, anti-PD-L1 antibody (200 mg, 3×/wk intraperitoneal) was given to inhibit PD-L1 activity during AVF maturation. Inhibition of PD-L1 increased T-helper type 1 cells and T-helper type 2 cells but reduced regulatory T cells to increase M1-type macrophages and reduce M2-type macrophages; these changes were associated with reduced vascular wall thickening and reduced AVF patency. Inhibition of PD-L1 also inhibited smooth muscle cell proliferation and increased endothelial dysfunction. The effects of anti-PD-L1 antibody on adaptive venous remodeling were diminished in nude mice; however, they were restored after T-cell transfer into nude mice, indicating the effects of anti-PD-L1 antibody on venous remodeling were dependent on T cells.

Conclusions: Regulation of PD-L1 activity may be a potential therapeutic target for clinical translation to improve AVF maturation.

Keywords: PD-L1; T cell; arteriovenous fistula; macrophages; venous remodeling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / physiology
  • Arteriovenous Shunt, Surgical
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / physiology*
  • Cell Differentiation*
  • Disease Models, Animal
  • Female
  • Kidney Failure, Chronic / therapy
  • Macrophages / physiology
  • Male
  • Mice
  • Mice, Nude
  • Renal Dialysis
  • T-Lymphocytes / physiology*
  • Vascular Remodeling / physiology*

Substances

  • Antibodies
  • B7-H1 Antigen
  • Cd274 protein, mouse