title: T cell ignorance is bliss: T cells are not tolerized by Langerhans cells presenting human papillomavirus antigens in the absence of costimulation.
abstract: Human papillomavirus type 16 (HPV16) infections are intra-epithelial, and thus, HPV16 is known to interact with Langerhans cells (LCs), the resident epithelial antigen-presenting cells (APCs). The current paradigm for APC-mediated induction of T cell anergy is through delivery of T cell receptor signals via peptides on MHC molecules (signal 1), but without costimulation (signal 2). We previously demonstrated that LCs exposed to HPV16in vitropresent HPV antigens to T cells without costimulation, but it remained uncertain if such T cells would remain ignorant, become anergic, or in the case of CD4+ T cells, differentiate into Tregs. Here we demonstrate that Tregs were not induced by LCs presenting only signal 1, and through a series ofin vitroimmunizations show that CD8+T cells receiving signal 1 + 2 from LCs weeks after consistently receiving signal 1 are capable of robust effector functions. Importantly, this indicates that T cells are not tolerized but instead remain ignorant to HPV, and are activated given the proper signals.
authors.affiliation: Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Woodham
authors.affiliation: Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Yan
authors.affiliation: Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Skeate
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Daniel
authors.initials: D
authors.lastname: van der Veen
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Heike H
authors.initials: HH
authors.lastname: Brand
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Wong
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Da Silva
authors.affiliation: Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, California, United States of America; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, California, United States of America.
authors.forename: W Martin
authors.initials: WM
authors.lastname: Kast
mesh_terms: D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000821:virology; D000956:Antigens, Viral / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016922:Cellular Senescence / Q000276:immunology; D018925:Chemokines / Q000276:immunology; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D052162:Human papillomavirus 16 / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000276:immunology; D007801:Langerhans Cells / Q000276:immunology*; D008213:Lymphocyte Activation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D018925:Chemokines; D061025:Costimulatory and Inhibitory T-Cell Receptors; D016207:Cytokines; D007376:Interleukin-2
keywords: HPV16; Human papillomavirus; Immune tolerance; Langerhans cells; T cell anergy; T cell ignorance