Dendritic cell maturation is required for the cross-tolerization of CD8+ T cells

Nat Immunol. 2001 Nov;2(11):1010-7. doi: 10.1038/ni722.

Abstract

In vivo models have shown that tissue-restricted antigen may be captured by bone marrow-derived cells and cross-presented for the tolerization of CD8+ T cells. Although these studies have shown peripheral tolerization of CD8+ T cells, the mechanism of antigen transfer and the nature of the antigen-presenting cell (APC) remain undefined. We report here the establishment of an in vitro system for the study of cross-tolerance and show that dendritic cells (DCs) phagocytose apoptotic cells and tolerize antigen-specific CD8+ T cells when cognate CD4+ T helper cells are absent. Using this system, we directly tested the "two-signal" hypothesis for the regulation of priming versus tolerance. We found that the same CD83+ myeloid-derived DCs were required for both cross-priming and cross-tolerance. These data suggested that the current model for peripheral T cell tolerance, "signal 1 in the absence of signal 2", requires refinement: the critical checkpoint is not DC maturation, but instead the presence of a third signal, which is active at the DC-CD4+ T cell interface.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Antigen Presentation
  • Antigens, CD
  • Antigens, Differentiation / pharmacology
  • Antigens, Viral / immunology
  • Apoptosis
  • CD28 Antigens / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD40 Antigens / immunology
  • CD40 Ligand / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD83 Antigen
  • CTLA-4 Antigen
  • Cell Communication
  • Cell Differentiation
  • Cells, Cultured
  • Coculture Techniques
  • Cross-Over Studies
  • Culture Media, Conditioned / chemistry
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • HLA-DR Antigens / immunology
  • Humans
  • Immune Tolerance / immunology*
  • Immunoconjugates*
  • Immunoglobulins / immunology
  • Interleukin-1 / pharmacology
  • Interleukin-12 / analysis
  • Interleukin-12 / pharmacology
  • Lymphocyte Activation / immunology*
  • Membrane Glycoproteins / immunology
  • Models, Immunological*
  • Orthomyxoviridae / immunology
  • Phagocytosis
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / analysis

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • Antigens, Viral
  • CD28 Antigens
  • CD40 Antigens
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Culture Media, Conditioned
  • HLA-DR Antigens
  • Immunoconjugates
  • Immunoglobulins
  • Interleukin-1
  • Membrane Glycoproteins
  • Tumor Necrosis Factor-alpha
  • CD40 Ligand
  • Interleukin-12
  • Abatacept