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Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy

2014; Nature Portfolio; Volume: 5; Issue: 1 Linguagem: Inglês

10.1038/ncomms5741

2041-1723

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

T-cell and B-cell Immunology

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.