PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy

Blood. 2017 Apr 13;129(15):2186-2197. doi: 10.1182/blood-2016-09-741629. Epub 2017 Feb 1.

Abstract

CD4+Foxp3+ regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after hematopoietic stem cell transplantation. We previously reported that low-dose interleukin-2 (IL-2) therapy increased circulating Tregs and improved clinical symptoms of chronic graft-versus-host-disease (cGVHD); however, the mechanisms that regulate Treg homeostasis during IL-2 therapy have not been well studied. To elucidate these regulatory mechanisms, we examined the role of inhibitory coreceptors on Tregs during IL-2 therapy in a murine model and in patients with cGVHD. Murine studies demonstrated that low-dose IL-2 selectively increased Tregs and simultaneously enhanced the expression of programmed cell death 1 (PD-1), especially on CD44+CD62L+ central-memory Tregs, whereas expression of other inhibitory molecules, including CTLA-4, LAG-3, and TIM-3 remained stable. PD-1-deficient Tregs showed rapid Stat5 phosphorylation and proliferation soon after IL-2 initiation, but thereafter Tregs became proapoptotic with higher Fas and lower Bcl-2 expression. As a result, the positive impact of IL-2 on Tregs was completely abolished, and Treg levels returned to baseline despite continued IL-2 administration. We also examined circulating Tregs from patients with cGVHD who were receiving low-dose IL-2 and found that IL-2-induced Treg proliferation was promptly followed by increased PD-1 expression on central-memory Tregs. Notably, clinical improvement of GVHD was associated with increased levels of PD-1 on Tregs, suggesting that the PD-1 pathway supports Treg-mediated tolerance. These studies indicate that PD-1 is a critical homeostatic regulator for Tregs by modulating proliferation and apoptosis during IL-2 therapy. Our findings will facilitate the development of therapeutic strategies that modulate Treg homeostasis to promote immune tolerance.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / immunology
  • Chronic Disease
  • Disease Models, Animal
  • Graft vs Host Disease / drug therapy*
  • Graft vs Host Disease / genetics
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / pathology
  • Hepatitis A Virus Cellular Receptor 2 / genetics
  • Hepatitis A Virus Cellular Receptor 2 / immunology
  • Immunologic Memory / drug effects*
  • Interleukin-2 / pharmacology*
  • Mice
  • Mice, Knockout
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • Phosphorylation / immunology
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / immunology
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • fas Receptor / genetics
  • fas Receptor / immunology

Substances

  • Antigens, CD
  • CD223 antigen
  • CTLA-4 Antigen
  • Fas protein, mouse
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Interleukin-2
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Proto-Oncogene Proteins c-bcl-2
  • STAT5 Transcription Factor
  • fas Receptor
  • Bcl2 protein, mouse