Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy

Nat Commun. 2014 Sep 3;5:4741. doi: 10.1038/ncomms5741.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • Autoantigens / administration & dosage*
  • Autoantigens / chemistry
  • Autoantigens / immunology
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / immunology
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / pathology
  • Clonal Anergy / drug effects
  • Complex Mixtures / administration & dosage
  • Complex Mixtures / immunology
  • Desensitization, Immunologic / methods*
  • Dose-Response Relationship, Immunologic
  • Encephalomyelitis, Autoimmune, Experimental / chemically induced
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Encephalomyelitis, Autoimmune, Experimental / therapy*
  • Female
  • Freund's Adjuvant / administration & dosage
  • Freund's Adjuvant / immunology
  • Gene Expression Regulation
  • Hepatitis A Virus Cellular Receptor 2
  • Injections, Subcutaneous
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology
  • Male
  • Mice
  • Mice, Transgenic
  • Peptides / administration & dosage*
  • Peptides / chemistry
  • Peptides / immunology
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • Proto-Oncogene Proteins c-maf / genetics
  • Proto-Oncogene Proteins c-maf / immunology
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology
  • Receptors, Virus / genetics
  • Receptors, Virus / immunology
  • Spinal Cord / chemistry
  • Transcriptome / drug effects*
  • Transcriptome / immunology

Substances

  • Antigens, CD
  • Autoantigens
  • Basic-Leucine Zipper Transcription Factors
  • CD223 antigen
  • Complex Mixtures
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • IL10 protein, mouse
  • Maf protein, mouse
  • Nfil3 protein, mouse
  • Pdcd1 protein, mouse
  • Peptides
  • Programmed Cell Death 1 Receptor
  • Proto-Oncogene Proteins c-maf
  • Receptors, Immunologic
  • Receptors, Virus
  • T cell Ig and ITIM domain protein, mouse
  • Interleukin-10
  • Freund's Adjuvant

Associated data

  • GEO/GSE46036