title: Negative regulation by PD-L1 during drug-specific priming of IL-22-secreting T cells and the influence of PD-1 on effector T cell function.
abstract: Activation of PD-1 on T cells is thought to inhibit Ag-specific T cell priming and regulate T cell differentiation. Thus, we sought to measure the drug-specific activation of naive T cells after perturbation of PD-L1/2/PD-1 binding and investigate whether PD-1 signaling influences the differentiation of T cells. Priming of naive CD4(+) and CD8(+) T cells against drug Ags was found to be more effective when PD-L1 signaling was blocked. Upon restimulation, T cells proliferated more vigorously and secreted increased levels of IFN-γ, IL-13, and IL-22 but not IL-17. Naive T cells expressed low levels of PD-1; however, a transient increase in PD-1 expression was observed during drug-specific T cell priming. Next, drug-specific responses from in vitro primed T cell clones and clones from hypersensitive patients were measured and correlated with PD-1 expression. All clones were found to secrete IFN-γ, IL-5, and IL-13. More detailed analysis revealed two different cytokine signatures. Clones secreted either FasL/IL-22 or granzyme B. The FasL/IL-22-secreting clones expressed the skin-homing receptors CCR4, CCR10, and CLA and migrated in response to CCL17/CCL27. PD-1 was stably expressed at different levels on clones; however, PD-1 expression did not correlate with the strength of the Ag-specific proliferative response or the secretion of cytokines/cytolytic molecules. This study shows that PD-L1/PD-1 binding negatively regulates the priming of drug-specific T cells. ELISPOT analysis uncovered an Ag-specific FasL/IL-22-secreting T cell subset with skin-homing properties.
authors: MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, England.
authors: Andrew
authors: A
authors: Gibson
authors: MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, England.
authors: Monday
authors: M
authors: Ogese
authors: MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, England.
authors: Andrew
authors: A
authors: Sullivan
authors: MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, England.
authors: Eryi
authors: E
authors: Wang
authors: MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, England.
authors: Katy
authors: K
authors: Saide
authors: Regional Adult Cystic Fibrosis Unit, St James's Hospital, Leeds, England.
authors: Paul
authors: P
authors: Whitaker
authors: Regional Adult Cystic Fibrosis Unit, St James's Hospital, Leeds, England.
authors: Daniel
authors: D
authors: Peckham
authors: MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, England.
authors: Lee
authors: L
authors: Faulkner
authors: MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, England.
authors: B Kevin
authors: BK
authors: Park
authors: MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, England.
authors: Dean J
authors: DJ
authors: Naisbitt
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000276:immunology / Q000494:pharmacology; D060890:B7-H1 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005436:Floxacillin / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D015848:Interleukin-5 / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D013420:Sulfamethoxazole / Q000031:analogs & derivatives / Q000276:immunology / Q000494:pharmacology; D055815:Young Adult; D000097043:Interleukin-22
chemical_list: D000900:Anti-Bacterial Agents; D060890:B7-H1 Antigen; D053222:Fas Ligand Protein; D005436:Floxacillin; D007371:Interferon-gamma; D018793:Interleukin-13; D007376:Interleukin-2; D015848:Interleukin-5; D007378:Interleukins; D061026:Programmed Cell Death 1 Receptor; D013420:Sulfamethoxazole; D000097043:Interleukin-22; C423236:CD274 protein, human; C505661:FASLG protein, human; C105992:PDCD1 protein, human; C072956:4-nitrososulfamethoxazole