Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy

Bronwen R Burton, Graham J Britton, Hai Fang, Johan Verhagen, Ben Smithers, Catherine A Sabatos-Peyton, Laura J Carney, Julian Gough, Stephan Strobel, David C Wraith

Research output: Contribution to journalArticlepeer-review

100 Citations (Scopus)
53 Downloads (Pure)

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.

Original languageEnglish
Article number4741
Pages (from-to)1-13
Number of pages13
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 3 Sep 2014

Keywords

  • Animals
  • Antigens, CD
  • Autoantigens
  • Basic-Leucine Zipper Transcription Factors
  • CD4-Positive T-Lymphocytes
  • Clonal Anergy
  • Complex Mixtures
  • Desensitization, Immunologic
  • Dose-Response Relationship, Immunologic
  • Encephalomyelitis, Autoimmune, Experimental
  • Female
  • Freund's Adjuvant
  • Gene Expression Regulation
  • Hepatitis A Virus Cellular Receptor 2
  • Injections, Subcutaneous
  • Interleukin-10
  • Male
  • Mice
  • Mice, Transgenic
  • Peptides
  • Programmed Cell Death 1 Receptor
  • Proto-Oncogene Proteins c-maf
  • Receptors, Immunologic
  • Receptors, Virus
  • Spinal Cord
  • Transcriptome
  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Immunotherapy
  • Molecular biology

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