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 and David C. Wraith ()
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Bronwen R. Burton: School of Cellular and Molecular Medicine, University of Bristol
Graham J. Britton: School of Cellular and Molecular Medicine, University of Bristol
Hai Fang: Computational Genomics Group, University of Bristol
Johan Verhagen: School of Cellular and Molecular Medicine, University of Bristol
Ben Smithers: Computational Genomics Group, University of Bristol
Catherine A. Sabatos-Peyton: School of Cellular and Molecular Medicine, University of Bristol
Laura J. Carney: School of Cellular and Molecular Medicine, University of Bristol
Julian Gough: Computational Genomics Group, University of Bristol
Stephan Strobel: Institute of Child Health, University College London
David C. Wraith: School of Cellular and Molecular Medicine, University of Bristol

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5741

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