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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antigens, CD / genetics
-
Antigens, CD / immunology
-
Autoantigens / administration & dosage*
-
Autoantigens / chemistry
-
Autoantigens / immunology
-
Basic-Leucine Zipper Transcription Factors / genetics
-
Basic-Leucine Zipper Transcription Factors / immunology
-
CD4-Positive T-Lymphocytes / drug effects*
-
CD4-Positive T-Lymphocytes / immunology
-
CD4-Positive T-Lymphocytes / pathology
-
Clonal Anergy / drug effects
-
Complex Mixtures / administration & dosage
-
Complex Mixtures / immunology
-
Desensitization, Immunologic / methods*
-
Dose-Response Relationship, Immunologic
-
Encephalomyelitis, Autoimmune, Experimental / chemically induced
-
Encephalomyelitis, Autoimmune, Experimental / immunology
-
Encephalomyelitis, Autoimmune, Experimental / pathology
-
Encephalomyelitis, Autoimmune, Experimental / therapy*
-
Female
-
Freund's Adjuvant / administration & dosage
-
Freund's Adjuvant / immunology
-
Gene Expression Regulation
-
Hepatitis A Virus Cellular Receptor 2
-
Injections, Subcutaneous
-
Interleukin-10 / genetics
-
Interleukin-10 / immunology
-
Lymphocyte Activation Gene 3 Protein
-
Male
-
Mice
-
Mice, Transgenic
-
Peptides / administration & dosage*
-
Peptides / chemistry
-
Peptides / immunology
-
Programmed Cell Death 1 Receptor / genetics
-
Programmed Cell Death 1 Receptor / immunology
-
Proto-Oncogene Proteins c-maf / genetics
-
Proto-Oncogene Proteins c-maf / immunology
-
Receptors, Immunologic / genetics
-
Receptors, Immunologic / immunology
-
Receptors, Virus / genetics
-
Receptors, Virus / immunology
-
Spinal Cord / chemistry
-
Transcriptome / drug effects*
-
Transcriptome / immunology
Substances
-
Antigens, CD
-
Autoantigens
-
Basic-Leucine Zipper Transcription Factors
-
Complex Mixtures
-
Havcr2 protein, mouse
-
Hepatitis A Virus Cellular Receptor 2
-
IL10 protein, mouse
-
Maf protein, mouse
-
Nfil3 protein, mouse
-
Pdcd1 protein, mouse
-
Peptides
-
Programmed Cell Death 1 Receptor
-
Proto-Oncogene Proteins c-maf
-
Receptors, Immunologic
-
Receptors, Virus
-
T cell Ig and ITIM domain protein, mouse
-
Interleukin-10
-
Freund's Adjuvant
-
Lymphocyte Activation Gene 3 Protein
-
Lag3 protein, mouse