Abstract

CD4 T cells reactive with beta-cell antigens play a key role in the pathogenesis and regulation of type 1 diabetes (T1D). With the exception of insulin, however, little is known of the antigens that drive CD4 T cells.

We have recently described two new autoantigens for diabetogenic CD4 T cells. Chromogranin A (ChgA) and islet amyloid polypeptide (IAPP) are both secretory proteins, and like insulin, are proteolytically cleaved within beta granules to generate active peptides. Under conditions of cellular stress, which are common to inflammatory states, peptides secreted from the beta granules may undergo modification, a process that can lead to neo-antigens.

Our data indicate that antigenicity of a T cell ligand from ChgA is greatly enhanced through enzymatic modification, suggesting that peptide ligands seen by autoreactive T cells in T1D may be products of post-translational modification. We have also identified an antigenic epitope from IAPP and this peptide has been used to develop a new tetramer reagent that can be used to track IAPP -reactive T cells.

New data indicate that both IAPP and ChgA-reactive T cells can be found in pre-diabetic NOD mice. Ligands from these two proteins are also being tested in antigen-specific tolerance induction strategies.