Tolerogenic dendritic cells impede priming of naïve CD8⁺ T cells and deplete memory CD8⁺ T cells

Eur J Immunol. 2013 Jan;43(1):85-92. doi: 10.1002/eji.201242879. Epub 2012 Nov 12.

Abstract

Type 1 diabetes is a T-cell-mediated autoimmune disease in which autoreactive CD8(+) T cells destroy the insulin-producing pancreatic beta cells. Vitamin D3 and dexamethasone-modulated dendritic cells (Combi-DCs) loaded with islet antigens inducing islet-specific regulatory CD4(+) T cells may offer a tissue-specific intervention therapy. The effect of Combi-DCs on CD8(+) T cells, however, remains unknown. To investigate the interaction of CD8(+) T cells with Combi-DCs presenting epitopes on HLA class I, naive, and memory CD8(+) T cells were co-cultured with DCs and proliferation and function of peptide-specific T cells were analyzed. Antigen-loaded Combi-DCs were unable to prime naïve CD8(+) T cells to proliferate, although a proportion of T cells converted to a memory phenotype. Moreover, expansion of CD8(+) T cells that had been primed by mature monocyte-derived DCs (moDCs) was curtailed by Combi-DCs in co-cultures. Combi-DCs expanded memory T cells once, but CD8(+) T-cell numbers collapsed by subsequent re-stimulation with Combi-DCs. Our data point that (re)activation of CD8(+) T cells by antigen-pulsed Combi-DCs does not promote, but rather deteriorates, CD8(+) T-cell immunity. Yet, Combi-DCs pulsed with CD8(+) T-cell epitopes also act as targets of cytotoxicity, which is undesirable for survival of Combi-DCs infused into patients in therapeutic immune intervention strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Cholecalciferol / immunology
  • Clonal Deletion
  • Coculture Techniques
  • Cytotoxicity, Immunologic
  • Dendritic Cells / immunology*
  • Dendritic Cells / transplantation*
  • Dexamethasone / immunology
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / therapy*
  • Epitopes, T-Lymphocyte / immunology
  • Epitopes, T-Lymphocyte / metabolism
  • HLA Antigens / metabolism
  • Humans
  • Immune Tolerance
  • Immunologic Memory
  • Lymphocyte Activation
  • Lymphocyte Depletion*
  • T-Lymphocyte Subsets / immunology*

Substances

  • Epitopes, T-Lymphocyte
  • HLA Antigens
  • Cholecalciferol
  • Dexamethasone