Immunosuppressive CD14+HLA-DRlow/neg IDO+ myeloid cells in patients following allogeneic hematopoietic stem cell transplantation

Leukemia. 2013 Feb;27(2):377-88. doi: 10.1038/leu.2012.215. Epub 2012 Jul 25.

Abstract

Myeloid-derived suppressor cells (MDSCs) have emerged as a heterogeneic immunoregulatory population that can expand in response to inflammatory signals. Predominantly studied in cancer, MDSCs suppress T cells utilizing various mechanisms. In allogeneic hematopoietic stem cell transplantation (allo-HSCT) therapy-related toxicity and alloreactivity increase inflammatory cytokines that might favor an MDSC accumulation. To address this question, circulating CD14(+)HLA-DR(low/neg) cells were studied retrospectively in 51 allo-HSCT patients. These cells represent one of the few well-described human MDSC subsets under physiological and pathological conditions. The frequency of CD14(+)HLA-DR(low/neg) cells was significantly increased after allo-HSCT, especially in patients with acute graft-versus-host disease. Compared to healthy donor cells they were pSTAT1(low) (phosphorylated signal transducer and activator of transcription) and indoleamine 2,3-dioxygenase (IDO)(high). Serum levels of granulocyte colony-stimulating factor and interleukin-6, which both have been linked to MDSC induction, correlated positively with the frequency of CD14(+)HLA-DR(low/neg) cells. In vitro dysfunction of patient T cells, such as reduced proliferative capacity or CD3ζ-chain expression, was rescued by blocking the IDO activity of CD14(+)HLA-DR(low/neg) cells. Overall, we identified a T-cell-suppressive monocytic population that expands after allo-HSCT. The mechanisms responsible for such accumulation remain to be elucidated. It will be of great interest to prospectively investigate the influence of these cells on the graft-versus-tumor and -host reaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Blotting, Western
  • Cell Proliferation
  • Cytokines / genetics
  • Cytokines / metabolism
  • Female
  • Flow Cytometry
  • Follow-Up Studies
  • Graft vs Host Disease / etiology*
  • Graft vs Host Disease / metabolism
  • Granulocyte Colony-Stimulating Factor / genetics
  • Granulocyte Colony-Stimulating Factor / metabolism
  • HLA-DR Antigens / metabolism*
  • Hematologic Neoplasms / complications*
  • Hematologic Neoplasms / immunology
  • Hematologic Neoplasms / therapy
  • Hematopoietic Stem Cell Transplantation / adverse effects*
  • Humans
  • Immunosuppression*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
  • Lipopolysaccharide Receptors / metabolism*
  • Male
  • Middle Aged
  • Monocytes / immunology
  • Monocytes / metabolism
  • Monocytes / pathology
  • Myeloid Cells / immunology*
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology
  • Oxidative Stress
  • Phosphorylation
  • Prognosis
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Retrospective Studies
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Transplantation, Autologous
  • Young Adult

Substances

  • Cytokines
  • HLA-DR Antigens
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Lipopolysaccharide Receptors
  • RNA, Messenger
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Granulocyte Colony-Stimulating Factor