Pancreatic islet antigen–Major Histocompatibility Complex (pMHC) (Islet pMHC)

Pancreatic islet antigen–Major Histocompatibility Complex (pMHC) complexes are the fundamental molecular units recognized by the immune system on the surface of insulin-producing beta cells. These complexes comprise fragments of islet-specific proteins—such as insulin, glutamic acid decarboxylase 65 (GAD65), and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)—bound to Human Leukocyte Antigen (HLA) molecules (Hull et al., 2020, JCI Insight). In Type 1 Diabetes, these pMHCs are the primary targets of autoreactive CD8+ and CD4+ T cells, leading to the progressive destruction of the pancreas's endocrine function (Tenspolde et al., 2019, Frontiers in Immunology). Therapeutic strategies involving engineered T-cell receptors (TCRs) leverage these complexes to redirect the immune response. For instance, TCR-engineered regulatory T cells (TCR-Tregs) are designed to recognize islet pMHCs to provide localized immunosuppression and promote self-tolerance without systemic side effects (Parvathy et al., 2021, Frontiers in Endocrinology). Conversely, pMHC-nanoparticles are being explored to expand endogenous regulatory populations by mimicking these target complexes to restore immune homeostasis.

Other names

Islet-specific peptide-MHC complexesBeta-cell antigen-HLA complexespMHC complexesInsulin-MHC complexGAD65-MHC complexIGRP-MHC complexPreproinsulin-HLA-A2 complex

Engineered T-cell receptors (TCRs) or TCR-like molecules bind specifically to the islet peptide-MHC complex on the surface of beta cells or antigen-presenting cells, facilitating targeted immune modulation, suppression of autoimmunity, or selective cell destruction.