Administration of anti-CD25 mAb leads to impaired α-galactosylceramide-mediated induction of IFN-γ production in a murine model

Immunobiology. 2013 Jun;218(6):851-9. doi: 10.1016/j.imbio.2012.10.012. Epub 2012 Oct 26.

Abstract

CD4(+)CD25(+)Foxp3(+) T regulatory cells (Tregs) and CD1d-restricted invariant natural killer T (iNKT) cells are two cell types that are known to regulate immune reactions. Depletion or inactivation of Tregs using specific anti-CD25 antibodies in combination with immunostimulation is an attractive modality especially in anti-tumour immunotherapy. However, CD25 is not expressed exclusively on Tregs but also on subpopulations of activated lymphocytes. Therefore, the modulatory effects of the specific anti-CD25 antibodies can also be partially attributed to their interactions with the effector cells. Here, the effector functions of iNKT cells were analysed in combination with anti-CD25 mAb PC61. Upon PC61 administration, α-galactosylceramide (α-GalCer)-mediated activation of iNKT cells resulted in decreased IFN-γ but not IL-4 production. In order to determine whether mutual interactions between Tregs and iNKT cells take place, we compared IFNγ production after α-GalCer administration in anti-CD25-treated and "depletion of regulatory T cell" (DEREG) mice. Since no profound effects on IFNγ induction were observed in DEREG mice, deficient in FoxP3(+) Tregs, our results indicate that the anti-CD25 antibody acts directly on CD25(+) effector cells. In vivo experiments demonstrated that although both α-GalCer and PC61 administration inhibited TC-1 tumour growth in mice, no additive/synergic effects were observed when these substances were used in combination therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology*
  • Antigens, CD1d / immunology
  • Antigens, CD1d / metabolism
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cell Line, Tumor
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Forkhead Transcription Factors / immunology
  • Forkhead Transcription Factors / metabolism
  • Galactosylceramides / administration & dosage
  • Galactosylceramides / immunology
  • Galactosylceramides / pharmacology*
  • Gene Expression / drug effects
  • Gene Expression / immunology
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / immunology
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology*
  • Interferon-gamma / metabolism
  • Interleukin-2 Receptor alpha Subunit / immunology*
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology
  • Interleukin-4 / metabolism
  • Kaplan-Meier Estimate
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Natural Killer T-Cells / drug effects*
  • Natural Killer T-Cells / immunology
  • Natural Killer T-Cells / metabolism
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / pathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Tumor Burden / drug effects
  • Tumor Burden / immunology

Substances

  • Antibodies, Monoclonal
  • Antigens, CD1d
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Galactosylceramides
  • Hbegf protein, mouse
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-2 Receptor alpha Subunit
  • PC61 monoclonal antibody
  • alpha-galactosylceramide
  • Interleukin-4
  • Interferon-gamma