Normal-tissue self peptide–Major Histocompatibility Complex (self-pMHC)

Normal-tissue self peptide–Major Histocompatibility Complex (MHC) complexes are molecular assemblies consisting of an endogenous peptide fragment bound to an MHC molecule on the surface of healthy cells. These complexes play a pivotal role in the immune system by facilitating central and peripheral tolerance, ensuring that T cells do not attack the body's own tissues (Janeway's Immunobiology, 9th ed.). In the field of immunotherapy, these complexes represent a critical anti-target or safety barrier; engineered T-cell receptors (TCRs) must be rigorously screened to ensure they do not cross-react with self-pMHCs found on vital organs (Nature Reviews Drug Discovery, 2016). For example, unintended recognition of a self-peptide from the protein titin in the heart led to lethal toxicity in early TCR-T clinical trials (Blood, 2013). Conversely, in autoimmune disease research, these complexes are studied as targets for tolerogenic therapies designed to suppress self-reactive immune responses (Frontiers in Immunology, 2021). Accurate mapping of the self-immunopeptidome via mass spectrometry is essential for predicting and preventing adverse events in next-generation biologics (Nature Communications, 2020). Overall, these complexes are fundamental to maintaining immunological homeostasis and are a primary consideration in the design of safe antigen-specific therapies.

Other names

Self-peptide MHC complexAutologous pMHCNormal tissue pMHCMHC-restricted self-antigenEndogenous pMHCSelf-pMHC

Recognition by T-cell receptors (TCRs) or TCR-like antibodies to either trigger immune effector functions or induce immunological tolerance.