Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10

Cancer Immunol Immunother. 2007 Jan;56(1):48-59. doi: 10.1007/s00262-006-0160-8. Epub 2006 Apr 13.

Abstract

CD4(+)CD25(+) regulatory T cells have been characterized as a critical population of immunosuppressive cells. They play a crucial role in cancer progression by inhibiting the effector function of CD4(+) or CD8(+) T lymphocytes. However, whether regulatory T lymphocytes that expand during tumor progression can modulate dendritic cell function is unclear. To address this issue, we have evaluated the inhibitory potential of CD4(+)CD25(+) regulatory T cells from mice bearing a BCR-ABL(+) leukemia on bone marrow-derived dendritic cells. We present data demonstrating that CD4(+)CD25(+)FoxP3(+) regulatory T cells from tumor-bearing animals impede dendritic cell function by down-regulating the activation of the transcription factor NF-kappaB. The expression of the co-stimulatory molecules CD80, CD86 and CD40, the production of TNF-alpha, IL-12, and CCL5/RANTES by the suppressed DC is strongly down-regulated. The suppression mechanism requires TGF-beta and IL-10 and is associated with induction of the Smad signaling pathway and activation of the STAT3 transcription factor.

Publication types

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

MeSH terms

  • Animals
  • B7-1 Antigen / metabolism
  • B7-2 Antigen / metabolism
  • Bone Marrow Cells
  • CD4 Antigens / immunology*
  • Dendritic Cells / physiology*
  • Female
  • Flow Cytometry
  • Forkhead Transcription Factors / metabolism
  • Fusion Proteins, bcr-abl / metabolism
  • Immunosuppression Therapy*
  • Interleukin-10 / metabolism*
  • Interleukin-2 Receptor alpha Subunit / immunology*
  • Leukemia / immunology
  • Leukemia / pathology
  • Leukemia / prevention & control
  • Lymphocyte Activation
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NF-kappa B / metabolism
  • Phosphorylation
  • Receptors, Transforming Growth Factor beta / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology*
  • Transforming Growth Factor beta / metabolism*

Substances

  • B7-1 Antigen
  • B7-2 Antigen
  • CD4 Antigens
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • NF-kappa B
  • Receptors, Transforming Growth Factor beta
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Transforming Growth Factor beta
  • Interleukin-10
  • Fusion Proteins, bcr-abl