Low-dose IL-2 selectively activates subsets of CD4+Tregs and NK cells.
CD4+regulatory T cells (CD4Tregs) play a critical role in the maintenance of immune tolerance and prevention of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. IL-2 supports the proliferation and survival of CD4Tregs and previous studies have demonstrated that IL-2 induces selective expansion of CD4Tregs and improves clinical manifestations of chronic GVHD. However, mechanisms for selective activation of CD4Tregs and the effects of low-dose IL-2 on other immune cells are not well understood. Using mass cytometry, we demonstrate that low concentrations of IL-2 selectively induce STAT5 phosphorylation in Helios+CD4Tregs and CD56brightCD16-NK cells in vitro. Preferential activation and expansion of Helios+CD4Tregs and CD56brightCD16-NK cells was also demonstrated in patients with chronic GVHD receiving low-dose IL-2. With prolonged IL-2 treatment for 48 weeks, phenotypic changes were also observed in Helios-CD4Tregs. The effects of low-dose IL-2 therapy on conventional CD4+T cells and CD8+T cells were limited to increased expression of PD-1 on effector memory T cells. These studies reveal the selective effects of low-dose IL-2 therapy on Helios+CD4Tregs and CD56brightNK cells that constitutively express high-affinity IL-2 receptors as well as the indirect effects of prolonged exposure to low concentrations of IL-2 in vivo.
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Masahiro
M
Hirakawa
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.|Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Tiago R
TR
Matos
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Hongye
H
Liu
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
John
J
Koreth
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
Haesook T
HT
Kim
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Nicole E
NE
Paul
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Kazuyuki
K
Murase
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.
Jennifer
J
Whangbo
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.|Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Ana C
AC
Alho
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Sarah
S
Nikiforow
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Corey
C
Cutler
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Vincent T
VT
Ho
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Philippe
P
Armand
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Edwin P
EP
Alyea
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Joseph H
JH
Antin
Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA.
Bruce R
BR
Blazar
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Joao F
JF
Lacerda
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Robert J
RJ
Soiffer
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Jerome
J
Ritz
D000328:Adult; D000368:Aged; D019002:CD56 Antigen / Q000378:metabolism; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D050799:STAT5 Transcription Factor / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*
D019002:CD56 Antigen; D007376:Interleukin-2; D050799:STAT5 Transcription Factor