A microenvironment-driven HLA-II-associated insulin neoantigen elicits persistent memory T cell activation in...

Area of Science:

• Immunology
• Endocrinology
• Molecular Biology

Background:

• Autoimmune diabetes involves a loss of self-tolerance, but the origin of new self-antigens (neoantigens) is unclear.
• Understanding neoantigen formation is crucial for developing targeted therapies for type 1 diabetes.

Purpose of the Study:

• To investigate the emergence of novel neoantigens in type 1 diabetes using an immunopeptidomics approach.
• To identify specific neoepitopes derived from pancreatic islets and their role in T cell-mediated autoimmunity.

Main Methods:

• Utilized an immunopeptidomics strategy to analyze HLA-II bound peptides from islet-derived sources in type 1 diabetes patients.
• Investigated the impact of oxidative remodeling on insulin and its presentation by antigen-presenting cells.

Main Results:

• Discovered a conserved Cys→Ser transformation (C19S) in insulin, altering self-reactivity at a single residue.
• Identified C19S as a neoepitope recognized by specific CD4+ T cells that expand during diabetes onset.
• Observed that these T cells exhibit a persistent memory phenotype and lack regulatory function.

Conclusions:

• A microenvironment-driven pathway generates neoantigens through oxidative insulin remodeling, contributing to sustained autoimmune responses in type 1 diabetes.
• The C19S neoepitope and associated T cell responses represent a key mechanism driving autoimmune diabetes pathogenesis.