Generation of Regulatory T Cells Against Islet Neoantigen

Area of Science:

• Immunology
• Endocrinology
• Autoimmunity

Background:

• Type 1 diabetes (T1D) involves T cell destruction of pancreatic beta-cells.
• Stress-induced neoantigens, arising from errors like ribosomal misreads, are implicated in autoimmunity.
• The role of neoantigens in peripheral immune regulation remains unclear.

Purpose of the Study:

• To investigate if regulatory T cells (Tregs) can be generated against the islet neoantigen INS-DRiP.
• To compare Tregs induced by neoantigen INS-DRiP with those induced by a native autoantigen (proinsulin-peptide C19A3).
• To assess the phenotype, cytokine profiles, and suppressive capacity of these induced Tregs.

Main Methods:

• Naïve CD4 T cells from healthy donors were isolated.
• T cells were co-cultured with monocyte-derived tolerogenic dendritic cells (DCs) pulsed with either neoantigen INS-DRiP or native autoantigen C19A3.
• Phenotypic analysis, cytokine profiling, and assessment of suppressive function were performed.

Main Results:

• Tregs generated against neoantigen INS-DRiP demonstrated complete inhibition of naïve T cell proliferation, comparable to Tregs induced by native autoantigen.
• Phenotypic and cytokine profiles showed Tregs specific to neoantigens and native autoantigens clustered together.
• Distinctive profiles were observed compared to T cells generated with proinflammatory DCs.

Conclusions:

• Naïve T cells reactive to islet neoantigens can be induced to become functional Tregs.
• Neoantigen-specific Tregs possess suppressive capacity similar to Tregs induced by native autoantigens.
• Harnessing immune regulation against neoantigens presents a promising strategy for T1D immune intervention or prevention.