title: Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy.
abstract: Antigen-specific immunotherapy combats autoimmunity or allergy by reinstating immunological tolerance to target antigens without compromising immune function. Optimization of dosing strategy is critical for effective modulation of pathogenic CD4(+) T-cell activity. Here we report that dose escalation is imperative for safe, subcutaneous delivery of the high self-antigen doses required for effective tolerance induction and elicits anergic, interleukin (IL)-10-secreting regulatory CD4(+) T cells. Analysis of the CD4(+) T-cell transcriptome, at consecutive stages of escalating dose immunotherapy, reveals progressive suppression of transcripts positively regulating inflammatory effector function and repression of cell cycle pathways. We identify transcription factors, c-Maf and NFIL3, and negative co-stimulatory molecules, LAG-3, TIGIT, PD-1 and TIM-3, which characterize this regulatory CD4(+) T-cell population and whose expression correlates with the immunoregulatory cytokine IL-10. These results provide a rationale for dose escalation in T-cell-directed immunotherapy and reveal novel immunological and transcriptional signatures as surrogate markers of successful immunotherapy.
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Bronwen R
authors.initials: BR
authors.lastname: Burton
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Britton
authors.affiliation: Computational Genomics Group, Department of Computer Science, University of Bristol, Bristol BS8 1UB, UK.
authors.forename: Hai
authors.initials: H
authors.lastname: Fang
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Johan
authors.initials: J
authors.lastname: Verhagen
authors.affiliation: Computational Genomics Group, Department of Computer Science, University of Bristol, Bristol BS8 1UB, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Smithers
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Sabatos-Peyton
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Carney
authors.affiliation: Computational Genomics Group, Department of Computer Science, University of Bristol, Bristol BS8 1UB, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Gough
authors.affiliation: Division of Biomedical Sciences, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Stephan
authors.initials: S
authors.lastname: Strobel
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Wraith
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D017635:Clonal Anergy / Q000187:drug effects; D045424:Complex Mixtures / Q000008:administration & dosage / Q000276:immunology; D003888:Desensitization, Immunologic / Q000379:methods*; D004306:Dose-Response Relationship, Immunologic; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D005260:Female; D005620:Freund's Adjuvant / Q000008:administration & dosage / Q000276:immunology; D005786:Gene Expression Regulation; D000072597:Hepatitis A Virus Cellular Receptor 2; D007279:Injections, Subcutaneous; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology; D013116:Spinal Cord / Q000737:chemistry; D059467:Transcriptome / Q000187:drug effects* / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D001324:Autoantigens; D050976:Basic-Leucine Zipper Transcription Factors; D045424:Complex Mixtures; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; C556062:IL10 protein, mouse; C495608:Maf protein, mouse; C497441:Nfil3 protein, mouse; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D051257:Proto-Oncogene Proteins c-maf; D011971:Receptors, Immunologic; D011991:Receptors, Virus; C556305:T cell Ig and ITIM domain protein, mouse; D016753:Interleukin-10; D005620:Freund's Adjuvant; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse