title: PD-1 signalling in CD4(+) T cells restrains their clonal expansion to an immunogenic stimulus, but is not critically required for peptide-induced tolerance.
abstract: The ultimate outcome of T-cell recognition of peptide-major histocompatibility complex (MHC) complexes is determined by the molecular context in which antigen presentation is provided. The paradigm is that, after exposure to peptides presented by steady-state dendritic cells (DCs), inhibitory signals dominate, leading to the deletion and/or functional inactivation of antigen-reactive T cells. This has been utilized in a variety of models providing peptide antigen in soluble form in the absence of adjuvant. A co-inhibitory molecule of considerable current interest is PD-1. Here we show that there is the opportunity for the PD-1/PD-L1 interaction to function in inhibiting the T-cell response during tolerance induction. Using traceable CD4(+) T-cell receptor (TCR) transgenic cells, together with a blocking antibody to disrupt PD-1 signalling, we explored the roles of PD-1 in the induction of tolerance versus a productive immune response. Intact PD-1 signalling played a role in limiting the extent of CD4(+) T-cell accumulation in response to an immunogenic stimulus. However, PD-1 signalling was not required for either the induction, or the maintenance, of peptide-induced tolerance; a conclusion underlined by successful tolerance induction in TCR transgenic cells genetically deficient for PD-1. These observations contrast with the reported requirement for PD-1 signals in CD8(+) T-cell tolerance.
authors.affiliation: Centre for Immunity Infection and Evolution, Institute of Immunology and Infection Research, Ashworth Laboratories, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Konkel
authors.forename: Friederike
authors.initials: F
authors.lastname: Frommer
authors.forename: Melanie D
authors.initials: MD
authors.lastname: Leech
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Anderton
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D000943:Antigens, Differentiation; C491383:Pdcd1 protein, mouse; D010446:Peptide Fragments; D061026:Programmed Cell Death 1 Receptor; C438947:ovalbumin (325-339); D010047:Ovalbumin