Molecular Interactions Governing Autoantigen Presentation in Type 1 Diabetes

Abstract

Type 1 diabetes is a chronic autoimmune disease resulting from T cell-mediated destruction of insulin-producing beta cells within pancreatic islets. Disease incidence has increased significantly in the last two decades, especially in young children. Type 1 diabetes is now predictable in humans with the measurement of serum islet autoantibodies directed against insulin and beta cell proteins. Knowledge regarding the presentation of insulin and islet antigens to T cells has increased dramatically over the last several years. Here, we review the trimolecular complex in diabetes, which consists of a major histocompatibility molecule,self-peptide, and T cell receptor, with a focus on insulin peptide presentation to T cells. With this increased understanding of how antigens are presented to T cells comes the hope for improved therapies for type 1 diabetes prevention.

Keywords: Autoimmunity; Diabetes; HLA; Insulin; T cells.

Fig. 1

The trimolecular complex is consists of the following: (1) major histocompatibility complex class II molecule, (2) peptide, and (3) T cell receptor on a CD4 T cell. The MHC is composed of a binding groove with pockets that can accommodate amino acid side chains (represented as arrows) of the peptide. This interaction with distinct structural pockets (pockets 1, 4, 6, and 9) anchors the peptide to the MHC class II molecule. The amino acid side chains of the peptide not binding to the MHC molecule can interact with a T cell receptor, thereby activating a T cell. P1–P9 denote pockets in the peptide binding groove. MHC major histocompatibility complex

Fig. 2

Position or “register” or insulin B chain amino acids 9–23 (B:9–23) binding to murine IA^g7 or human HLA-DQ8. The amino acids in red are contact residues for MHC class II at position 1, 4, 6 and 9, while the remaining amino acids in black are potential T cell receptor contacts. Each register creates a distinct epitope for T cell recognition even though the peptide is insulin B:9–23 in each case

Fig. 3

T cell receptor (TCR) V gene skewing in response to an insulin B:9–23 mimotope. a Data for Vα gene sequencing before and after stimulation from three T1D subjects all with identical DQ alleles. TCR alpha chain genes were sequenced to identify V gene usage from CD4 T cells prior to and after proliferation to the insulin mimotope. Data are depicted as the fold change (proliferated/baseline) for each V gene and show the mean +/− SEM. b Phylogenetic trees of V genes, created using the Clustal-Omega algorithm, based upon similarity in CDR1. c CDR2 regions. Four predominant V genes (highlighted and red) in the proliferated cells of all 3 patients cluster together based upon similarity in CDR1 and CDR2 sequences