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.
Original language | English |
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Article number | 4741 |
Pages (from-to) | 1-13 |
Number of pages | 13 |
Journal | Nature Communications |
Volume | 5 |
DOIs | |
Publication status | Published - 3 Sept 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