Tryptophan deprivation induces inhibitory receptors ILT3 and ILT4 on dendritic cells favoring the induction of human CD4+CD25+ Foxp3+ T regulatory cells.
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.
Brenk
Manuela
M
Department of Dermatology and Allergy, Friedrich-Wilhelms-University of Bonn, Germany.
Scheler
Marina
M
Koch
Susanne
S
Neumann
Jürgen
J
Takikawa
Osamu
O
Häcker
Georg
G
Bieber
Thomas
T
von Bubnoff
Dagmar
D
D015704:CD4 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D007108:Immune Tolerance; D016130:Immunophenotyping; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D009000:Monocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000502:physiology; D011971:Receptors, Immunologic / Q000096:biosynthesis*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014364:Tryptophan / Q000172:deficiency / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology
D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053645:Interleukin-2 Receptor alpha Subunit; C491341:LILRB2 protein, human; C107907:LILRB4 protein, human; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D014364:Tryptophan; C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases