Self peptide–Major Histocompatibility Complex (MHC) (self-pMHC)

Self peptide–Major Histocompatibility Complex (MHC) complexes are molecular assemblies consisting of a host-derived peptide fragment bound to an MHC Class I or Class II molecule, displayed on the surface of healthy cells (Murphy & Weaver, Janeway's Immunobiology, 2016). Their primary biological function is the maintenance of self-tolerance, a process initiated in the thymus where T cells that react too strongly to self-pMHC are eliminated or diverted into regulatory lineages (Hogquist et al., Nature Reviews Immunology, 2005). In autoimmune diseases, such as Type 1 Diabetes or Multiple Sclerosis, this tolerance fails, and the immune system mistakenly targets these complexes on normal tissues (Bluestone et al., Nature, 2010). In the field of oncology, self-pMHC complexes on normal tissues represent a critical safety hurdle for engineered T-cell therapies; if a therapeutic T-cell receptor (TCR) cross-reacts with a self-peptide presented on healthy organs, it can lead to severe "on-target, off-tumor" toxicity (Linette et al., Blood, 2013). Current drug development efforts focus on either inducing tolerance to these complexes using tolerogenic vaccines to restore immune balance or ensuring high specificity of engineered receptors to avoid them entirely (Steinman et al., Nature Reviews Drug Discovery, 2003).

Other names

Self-antigen-MHC complexAutologous peptide-MHCSelf-pMHC complexEndogenous peptide-MHCNormal tissue pMHC

Modulation of T-cell receptor (TCR) signaling to induce immune tolerance, anergy, or regulatory T-cell (Treg) expansion, or the avoidance of cross-reactive recognition by engineered immune cells (Murphy & Weaver, Janeway's Immunobiology, 2016).