Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy

Abstract

Antigen-specific immunotherapy combats autoimmunity or allergy by reinstating immunological tolerance to target antigens without compromising immune function. Optimisation 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, 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 characterise 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.

TIGIT Enhances Antigen-Specific Th2 Recall Responses and Allergic Disease

“…4A, 4C). In different settings, TIGIT ligation enhanced IL-10 production by T cells (5,7,24), which was consistent with our observation of reduced IL-10 secretion upon either TIGIT or CD155 blockade (Fig. 4A, 4C).…”

Proinsulin multi-peptide immunotherapy induces antigen-specific regulatory T cells and limits autoimmunity in a humanized model

“…Human diseases for which peptide-based immunotherapies are under investigation include clinical allergy, rheumatoid arthritis, multiple sclerosis and type 1 diabetes [9][10][11][12]. Early-stage development of PIT in the relevant clinical setting has provided encouraging indications that this approach has the ability to modify the autoimmune response, via analysis of both surrogate and clinical outcomes.…”

Peptide immunotherapy in experimental autoimmune encephalomyelitis

“…Time-course sampling and Affymetrix GeneChip analysis not only confirmed the gain in IL-10 expression, but also demonstrated dynamic changes in the expression of a range of cell surface molecules, transcription factors and genes involved in cell cycle activity. [71] The transcription factors Maf and Nfil3 were strongly elevated by dose-escalation PIT and these are positively associated with IL-10 production. [72][73][74] IL-21 production was also elevated in PIT-exposed T cells, which is again consistent with induction of IL-10.…”

“…Of note in this context, no combination of the above surface markers could specifically discern IL-10-producing T cells. [71] Another important question is how is the inability to produce proinflammatory cytokines driven by PIT in this scenario. Is this dependent on IL-10, or, as seems likely, do other gene changes determine this?…”