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*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

107 Citations (Scopus)

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. © 2014 Macmillan Publishers Limited. All rights reserved.

Original languageEnglish
Article number4741
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 3 Sep 2014

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