Characterization of human T cells that regulate neutrophilic skin inflammation.
It is unknown whether neutrophilic inflammations can be regulated by T cells. This question was analyzed by studying acute generalized exanthematous pustulosis (AGEP), which is a severe drug hypersensitivity resulting in intraepidermal or subcorneal sterile pustules. Recently, we found that drug-specific blood and skin T cells from AGEP patients secrete high levels of the potent neutrophil-attracting chemokine IL-8/CXCL8. In this study, we characterize the phenotype and function of CXCL8-producing T cells. Supernatants from CXCL8(+) T cells were strongly chemotactic for neutrophils, CXCR1, and CXCR2 transfectants, but not for transfectants expressing CXCR4, CX3CR1, human chemokine receptor, and RDC1. Neutralization experiments indicated that chemotaxis was mainly mediated by CXCL8, but not by granulocyte chemotactic protein-2/CXCL6, epithelial cell-derived neutrophil attractant-78/CXCL5, or growth-related oncogene-alpha,beta,gamma/CXCL1,2,3. Interestingly, approximately 2.5% of CD4(+) T cells in normal peripheral blood also produced CXCL8. In addition to CXCL8, AGEP T cells produced large amounts of the monocyte/neutrophil-activating cytokine GM-CSF, and the majority released IFN-gamma and the proinflammatory cytokine TNF-alpha. Furthermore, apoptosis in neutrophils treated with conditioned medium from CXCL8(+) T cells could be reduced by 40%. In lesional skin, CXCL8(+) T cells consistently expressed the chemokine receptor CCR6, suggesting a prominent role for CCR6 in early inflammatory T cell recruitment. Finally, our data suggest that CXCL8-producing T cells facilitate skin inflammation by orchestrating neutrophilic infiltration and ensuring neutrophil survival, which leads to sterile pustular eruptions found in AGEP patients. This mechanism may be relevant for other T cell-mediated diseases with a neutrophilic inflammation such as Behçet's disease and pustular psoriasis.
Schaerli
Patrick
P
Division of Allergology, Clinic of Rheumatology and Clinical Immunology/Allergology, Inselspital, and Theodor-Kocher-Institute, University of Bern, Switzerland.
Britschgi
Markus
M
Keller
Monika
M
Steiner
Urs C
UC
Steinmann
Lisa S
LS
Moser
Bernhard
B
Pichler
Werner J
WJ
D000208:Acute Disease; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D002470:Cell Survival; D002478:Cells, Cultured / Q000276:immunology / Q000378:metabolism; D019743:Chemokines, CXC / Q000032:analysis* / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003875:Drug Eruptions / Q000209:etiology / Q000276:immunology*; D005076:Exanthema / Q000139:chemically induced / Q000276:immunology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis* / Q000502:physiology; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D054387:Receptors, CXCR; D019718:Receptors, CXCR4 / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D023062:Receptors, Interleukin-8A / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000235:genetics; D012867:Skin / Q000276:immunology; D012872:Skin Diseases, Vesiculobullous / Q000139:chemically induced / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C501896:ACKR3 protein, human; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D019743:Chemokines, CXC; C501897:Cmkor1 protein, mouse; D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D015759:Ionomycin; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate