TY - JOUR
T1 - PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy
AU - Asano, Takeru
AU - Meguri, Yusuke
AU - Yoshioka, Takanori
AU - Kishi, Yuriko
AU - Iwamoto, Miki
AU - Nakamura, Makoto
AU - Sando, Yasuhisa
AU - Yagita, Hideo
AU - Koreth, John
AU - Kim, Haesook T.
AU - Alyea, Edwin P.
AU - Armand, Philippe
AU - Cutler, Corey S.
AU - Ho, Vincent T.
AU - Antin, Joseph H.
AU - Soiffer, Robert J.
AU - Maeda, Yoshinobu
AU - Tanimoto, Mitsune
AU - Ritz, Jerome
AU - Matsuoka, Ken Ichi
N1 - Funding Information:
This work was supported by Japan Society for the Promotion of Science KAKENHI Grant No. 26461449 and the National Institutes of Health, National Cancer Institute grants P01CA142106, CA183559, and CA183560.
Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/4/13
Y1 - 2017/4/13
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2016-09-741629
DO - 10.1182/blood-2016-09-741629
M3 - Article
C2 - 28151427
AN - SCOPUS:85021308822
VL - 129
SP - 2186
EP - 2197
JO - Blood
JF - Blood
SN - 0006-4971
IS - 15
ER -