title: β-Lactam hypersensitivity involves expansion of circulating and skin-resident TH22 cells.
abstract: β-Lactam hypersensitivity has been classified according to the phenotype and function of drug-specific T cells. However, new T-cell subsets have not been considered.
  
  
  
  The objective of this study was to use piperacillin as a model of β-lactam hypersensitivity to study the nature of the drug-specific T-cell response induced in the blood and skin of hypersensitive patients and healthy volunteers.
  
  
  
  Drug-specific T cells were cloned from blood and inflamed skin, and cellular phenotype and function were explored. Naive T cells from healthy volunteers were primed to piperacillin, cloned, and subjected to the similar analyses.
  
  
  
  PBMC and T-cell clones (n = 570, 84% CD4+) from blood of piperacillin-hypersensitive patients proliferated and secreted TH1/TH2 cytokines alongside IL-22 after drug stimulation. IL-17A secretion was not detected. Drug-specific clones from inflamed skin (n = 96, 83% CD4+) secreted a similar profile of cytokines but displayed greater cytolytic activity, secreting perforin, granzyme B, and Fas ligand when activated. Blood- and skin-derived clones expressed high levels of skin-homing chemokine receptors and migrated in the presence of the ligands CCL17 and CCL27. Piperacillin-primed naive T cells from healthy volunteers also secreted IFN-γ, IL-13, IL-22, and cytolytic molecules. Aryl hydrocarbon receptor blockade prevented differentiation of the naive T cells into antigen-specific IL-22-secreting cells.
  
  
  
  Together, our results reveal that circulating and skin-resident, antigen-specific, IL-22-secreting T cells are detectable in patients with β-lactam hypersensitivity. Furthermore, differentiation of naive T cells into antigen-specific TH22 cells is dependent on aryl hydrocarbon receptor signaling.
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sullivan
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Eryi
authors.initials: E
authors.lastname: Wang
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Farrell
authors.affiliation: Regional Adult Cystic Fibrosis Unit, St James's Hospital, Leeds, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Whitaker
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Lee
authors.initials: L
authors.lastname: Faulkner
authors.affiliation: Regional Adult Cystic Fibrosis Unit, St James's Hospital, Leeds, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Peckham
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom. Electronic address: dnes@liv.ac.uk.
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Naisbitt
mesh_terms: D000941:Antigens / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004342:Drug Hypersensitivity / Q000097:blood* / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D010878:Piperacillin / Q000009:adverse effects; D015398:Signal Transduction; D012867:Skin / Q000166:cytology* / Q000276:immunology*; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D047090:beta-Lactams / Q000009:adverse effects*
chemical_list: D000941:Antigens; D016207:Cytokines; D047090:beta-Lactams; D010878:Piperacillin
keywords: Human; T cells; drug hypersensitivity