Major histocompatibility complex class I–peptide complex (pMHC I) (pMHC I)

The Major Histocompatibility Complex class I (MHC I)–peptide complex is a molecular assembly consisting of a polymorphic heavy chain, beta-2 microglobulin, and an 8-10 amino acid peptide [1]. On dendritic cells, these complexes are essential for the "cross-presentation" of exogenous antigens, a process required to prime naive CD8+ T cells into active cytotoxic T lymphocytes (CTLs) [2]. This interaction between the pMHC I on the dendritic cell and the T-cell receptor (TCR) on the CD8+ T cell dictates the specificity and strength of the adaptive immune response [1]. In therapeutic contexts, the pMHC I complex is targeted by TCR-engineered T cells (TCR-T) and bispecific molecules like Tebentafusp, which redirect T cells to recognize specific tumor-associated peptides [3, 4]. These therapies are particularly effective in treating cancers where traditional antibodies cannot reach intracellular targets because MHC I presents fragments of internal proteins on the cell surface [1]. However, the high degree of HLA polymorphism requires patient-specific HLA typing for treatment eligibility [3]. Furthermore, the potential for off-target cross-reactivity with similar self-peptides in healthy tissues presents a significant safety challenge, as seen in early TCR trials [5]. Despite these challenges, targeting the pMHC I complex remains a frontier in precision oncology and vaccine development [4]. Citations: [1] Rock KL, et al. (2016). Immunity. [2] Joffre OP, et al. (2012). Nature Reviews Immunology. [3] Nathan P, et al. (2021). NEJM. [4] D'Angelo SP, et al. (2018). Cancer Discovery. [5] Linette GP, et al. (2013). Blood.

Other names

HLA-peptide complexAntigen-MHC I complexpMHCMHC-I-restricted antigen

T-cell receptor (TCR) mediated recognition of the peptide-MHC complex, leading to the formation of an immunological synapse and subsequent activation of cytotoxic T cell effector functions [1, 2].