Generation of Regulatory T Cells Against Islet Neoantigen

Type 1 diabetes (T1D) results from T cell-mediated destruction of insulin-producing pancreatic beta-cells. Recently, the immune-provoking role of stress-related neoantigens has become evident. Neoantigens unlikely contribute to central tolerance and therefore hold strong immunogenic potential, but their role in peripheral immune regulation is unknown. Here, we sought proof of concept that Tregs can be generated against islet neoantigen INS-DRiP that results from stress-induced ribosomal misreads of insulin mRNA. Tregs were induced from naïve CD4 T cells isolated from a healthy donor and co-cultured with monocyte-derived tolerogenic DCs either pulsed with neoantigen INS-DRiP or native autoantigen (proinsulin-peptide C19A3) that can induce Tregs in T1D patients. Their phenotypes, cytokine profiles and suppressive capacity were compared. Tregs induced against neoantigen completely inhibited proliferation of naïve T cells upon cognate antigen-pulsed DC stimulation, which was indistinguishable from Tregs induced against C19A3. Phenotype and cytokine profiling showed co-clustering of native autoantigen- and neoantigen-specific Tregs, and distinction from T cells generated with antigen-pulsed proinflammatory instead of tolerogenic DCs. Naïve T cells exist against islet neoantigen that can be primed to become Tregs despite the high immunogenic potential of neoantigen. Induction of immune regulation to neoantigens may be useful as immune intervention or prevention of T1D.