Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy

Research output: Contribution to journalArticlepeer-review

Authors

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

Colleges, School and Institutes

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.

Details

Original languageEnglish
Article number4741
Pages (from-to)1-13
Number of pages13
JournalNature Communications
Volume5
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