Tryptophan deprivation induces inhibitory receptors ILT3 and ILT4 on dendritic cells favoring the induction of human CD4+CD25+ Foxp3+ T regulatory cells

J Immunol. 2009 Jul 1;183(1):145-54. doi: 10.4049/jimmunol.0803277. Epub 2009 Jun 17.

Abstract

Tryptophan catabolism through IDO activity can cause nonresponsiveness and tolerance acting on T cells. Given the crucial importance of dendritic cells (DCs) in the initiation of a T cell response, surprisingly little is known about the impact of IDO activity and tryptophan deprivation on DCs themselves. In the present study, we show that human DCs differentiated under low-tryptophan conditions acquire strong tolerogenic capacity. This effect is associated with a markedly decreased Ag uptake as well as the down-regulation of costimulatory molecules (CD40, CD80). In contrast, the inhibitory receptors ILT3 and ILT4 are significantly increased. Functionally, tryptophan-deprived DCs show a reduced capacity to stimulate T cells, which can be restored by blockade of ILT3. Moreover, ILT3(high)ILT4(high) DCs lead to the induction of CD4(+)CD25(+) Foxp3(+) T regulatory cells with suppressive activity from CD4(+)CD25(-) T cells. The generation of ILT3(high)ILT4(high) DCs with tolerogenic properties by tryptophan deprivation is linked to a stress response pathway mediated by the GCN2 kinase. These results demonstrate that tryptophan degradation establishes a regulatory microenvironment for DCs, enabling these cells to induce T regulatory cells. The impact of IDO thus extends beyond local immune suppression to a systemic control of the immune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4 Antigens / biosynthesis
  • Cell Differentiation / immunology*
  • Cells, Cultured
  • Coculture Techniques
  • Dendritic Cells / enzymology
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Forkhead Transcription Factors / biosynthesis
  • Humans
  • Immune Tolerance
  • Immunophenotyping
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Interleukin-2 Receptor alpha Subunit / biosynthesis
  • Membrane Glycoproteins / biosynthesis*
  • Monocytes / enzymology
  • Monocytes / immunology
  • Monocytes / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology
  • Receptors, Cell Surface / biosynthesis*
  • Receptors, Cell Surface / physiology
  • Receptors, Immunologic / biosynthesis*
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*
  • Tryptophan / deficiency
  • Tryptophan / metabolism*
  • Up-Regulation / immunology

Substances

  • CD4 Antigens
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Interleukin-2 Receptor alpha Subunit
  • LILRB2 protein, human
  • LILRB4 protein, human
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Tryptophan
  • EIF2AK4 protein, human
  • Protein-Serine-Threonine Kinases