Regulation of the class II MHC pathway in primary human monocytes by granulocyte-macrophage colony-stimulating factor

J Immunol. 2003 Sep 1;171(5):2374-83. doi: 10.4049/jimmunol.171.5.2374.

Abstract

GM-CSF stimulates the growth and differentiation of hematopoietic progenitors and also affects mature cell function. These effects have led to the use of GM-CSF as a vaccine adjuvant with promising results; however, the mechanisms underlying GM-CSF-mediated immune potentiation are incompletely understood. In this study, we investigated the hypothesis that the immune stimulatory role of GM-CSF is in part due to effects on class II MHC Ag presentation. We find that, in primary human monocytes treated for 24-48 h, GM-CSF increases surface class II MHC expression and decreases the relative level of the invariant chain-derived peptide, CLIP, bound to surface class II molecules. GM-CSF also increases expression of the costimulatory molecules CD86 and CD40, but not the differentiation marker CD1a or CD16. Furthermore, GM-CSF-treated monocytes are better stimulators in a mixed leukocyte reaction. Additional analyses of the class II pathway revealed that GM-CSF increases total protein and RNA levels of HLA-DR, DM, and DOalpha. Expression of class II transactivator (CIITA) types I and III, but not IV, transcripts increases in response to GM-CSF. Furthermore, GM-CSF increases the amount of CIITA associated with the DR promoter. Thus, our data argue that the proinflammatory role of GM-CSF is mediated in part through increased expression of key molecules involved in the class II MHC pathway via induction of CIITA.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adjuvants, Immunologic / pharmacology
  • Antigen Presentation / immunology
  • Antigens, CD / biosynthesis
  • Antigens, Differentiation, B-Lymphocyte / biosynthesis
  • Antigens, Differentiation, B-Lymphocyte / genetics
  • Antigens, Differentiation, B-Lymphocyte / metabolism
  • B7-2 Antigen
  • CD40 Antigens / biosynthesis
  • Cell Differentiation / immunology
  • Cell Membrane / immunology
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Down-Regulation / genetics
  • Down-Regulation / immunology
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology*
  • HLA-D Antigens / biosynthesis
  • HLA-D Antigens / genetics
  • HLA-D Antigens / metabolism*
  • HLA-D Antigens / physiology
  • HLA-DR Antigens / biosynthesis
  • HLA-DR Antigens / genetics
  • HLA-DR Antigens / metabolism
  • HLA-DR alpha-Chains
  • Histocompatibility Antigens Class II / biosynthesis
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / pharmacology
  • Interleukin-10 / antagonists & inhibitors
  • Interleukin-10 / biosynthesis
  • Membrane Glycoproteins / biosynthesis
  • Monocytes / cytology
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Promoter Regions, Genetic
  • RNA, Messenger / biosynthesis
  • Recombinant Proteins
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Transcription, Genetic / immunology
  • Up-Regulation / genetics
  • Up-Regulation / immunology

Substances

  • Adjuvants, Immunologic
  • Antigens, CD
  • Antigens, Differentiation, B-Lymphocyte
  • B7-2 Antigen
  • CD40 Antigens
  • CD86 protein, human
  • HLA-D Antigens
  • HLA-DM antigens
  • HLA-DO antigens
  • HLA-DR Antigens
  • HLA-DR alpha-Chains
  • Histocompatibility Antigens Class II
  • Membrane Glycoproteins
  • RNA, Messenger
  • Recombinant Proteins
  • invariant chain
  • Interleukin-10
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor