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

• Published in: Blood Vol. 129; no. 15; pp. 2186 - 2197
• Main Authors: Asano, Takeru, Meguri, Yusuke, Yoshioka, Takanori, Kishi, Yuriko, Iwamoto, Miki, Nakamura, Makoto, Sando, Yasuhisa, Yagita, Hideo, Koreth, John, Kim, Haesook T., Alyea, Edwin P., Armand, Philippe, Cutler, Corey S., Ho, Vincent T., Antin, Joseph H., Soiffer, Robert J., Maeda, Yoshinobu, Tanimoto, Mitsune, Ritz, Jerome, Matsuoka, Ken-ichi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13-04-2017; American Society of Hematology
• Subjects: Animals; Antigens, CD - genetics; Antigens, CD - immunology; Chronic Disease; CTLA-4 Antigen - genetics; CTLA-4 Antigen - immunology; Disease Models, Animal; fas Receptor - genetics; fas Receptor - immunology; 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; Transplantation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2016-09-741629

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.
•IL-2 induces expression of PD-1 on Tregs, and PD-1 blockade promotes Treg differentiation and apoptosis.•PD-1 regulates IL-2–induced Treg proliferation and prolongs Treg survival in murine models and in patients receiving low-dose IL-2 therapy.