Journal
NATURE COMMUNICATIONS
Volume 5, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms5741
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Funding
- Wellcome Trust [091074/z/09/z, 086779/Z/08/A]
- MS Society UK [900/08]
- Batchworth Trust
- University of Bristol
- Biotechnology and Biological Sciences Research Council [BB/G022771/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [1247165] Funding Source: researchfish
- Wellcome Trust [086779/Z/08/A, 091074/Z/09/Z] Funding Source: Wellcome Trust
- BBSRC [BB/G022771/1] Funding Source: UKRI
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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.
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