Making the Most of Major Histocompatibility Complex Molecule Multimers: Applications in Type 1 Diabetes

Abstract

Classical major histocompatibility complex (MHC) class I and II molecules present peptides to cognate T-cell receptors on the surface of T lymphocytes. The specificity with which T cells recognize peptide-MHC (pMHC) complexes has allowed for the utilization of recombinant, multimeric pMHC ligands for the study of minute antigen-specific T-cell populations. In type 1 diabetes (T1D), CD8+ cytotoxic T lymphocytes, in conjunction with CD4+ T helper cells, destroy the insulin-producing β cells within the pancreatic islets of Langerhans. Due to the importance of T cells in the progression of T1D, the ability to monitor and therapeutically target diabetogenic clonotypes of T cells provides a critical tool that could result in the amelioration of the disease. By administering pMHC multimers coupled to fluorophores, nanoparticles, or toxic moieties, researchers have demonstrated the ability to enumerate, track, and delete diabetogenic T-cell clonotypes that are, at least in part, responsible for insulitis; some studies even delay or prevent diabetes onset in the murine model of T1D. This paper will provide a brief overview of pMHC multimer usage in defining the role T-cell subsets play in T1D etiology and the therapeutic potential of pMHC for antigen-specific identification and modulation of diabetogenic T cells.

Inducing immune tolerance: a focus on Type 1 diabetes mellitus

“…The generation and use of multimeric pMHCs, such as tetramers, are powerful tools used to address T-cell dynamics, distribution and allow phenotypic characterization of Ag-specific T cells [136,137]. The use of pMHC multimers has also been applied for the prediction and treatment of T1D [138,139]. Treatment with pMHC dimers prevented autoimmunity in two transfer models of T1D by inducing IL-10-dependent Tregs [140,141].…”

Mechanism of Action of Oral Salmonella-Based Vaccine to Prevent and Reverse Type 1 Diabetes in NOD Mice

“…In experimental models of diabetes, a tolerating immune response against autoantigens prevented further beta-cell destruction [ 8 , 24 ]. Approaches to generate tolerance in pre-clinical T1D included the deletion of alloantigen [ 25 ], tetramer and peptide therapy [ 26 ], depletion of effector cells [ 27 ], inhibition of immune activation molecules, expression of cell membrane suppressor molecules (PD-1, CTLA-4, and CD47) [ 28 ], and expansion of regulatory T-cells [ 29 ].…”