Allergen-driven suppression of thiol production by human dendritic cells and the effect of thiols on T cell function.
Dendritic cells are a major source of extracellular thiols needed for T cell activation, a process in which CD40-mediated stimulation plays a pivotal role. The Dermatophagoides pteronyssinus group 1 mite allergen (Der p 1) has previously been shown to cleave CD40 from the surface of human dendritic cells, thereby suggesting that Der p 1 might compromise the ability of these cells to sustain thiol production during T cell activation. This has therefore prompted us to examine the effect of the mite protease allergen Der p 1 on thiol production by human dendritic cells. Monocyte-derived dendritic cells were treated with either proteolytically active or inactive Der p 1 and then stimulated through CD40 for extracellular thiol detection. The effect of thiol (N-acetyl-l-cysteine) and thiol inhibitors on naïve T cell responses, including CD25 and FOXP3 expressions, cell proliferation and cytokine production, was determined. Here, we show that Der p 1-mediated cleavage of CD40 from the surface of dendritic cells suppresses the ability of these cells to produce extracellular thiols, and that reducing thiols are needed for the generation of the T helper type 1 (Th1), T cytotoxic type 1 (Tc1) and T regulatory (Treg) cell phenotypes. We conclude that Der p 1-driven suppression of thiol production by dendritic cells may disrupt Th1/Tc1 and Treg cell development, and in doing so could lead to Th2/Tc2 cell responses and allergy.
Hasan
Amal A
AA
Institute of Infection, Immunity and Inflammation, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Ghaemmaghami
Amir M
AM
Fairclough
Lucy
L
Robins
Adrian
A
Sewell
Herb F
HF
Shakib
Farouk
F
D000111:Acetylcysteine / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology / Q000494:pharmacology*; D060829:Arthropod Proteins; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D040002:Dermatophagoides pteronyssinus / Q000276:immunology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D039741:Antigens, Dermatophagoides; D060829:Arthropod Proteins; D019013:CD40 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D003546:Cysteine Endopeptidases; C451162:Dermatophagoides pteronyssinus antigen p 1; D000111:Acetylcysteine