Human Leukocyte Antigen class I and class II peptide-binding domains (HLA class I/II PBDs)

The Human Leukocyte Antigen (HLA) class I and class II peptide-binding domains are the specialized structural regions of the Major Histocompatibility Complex (MHC) responsible for presenting processed peptide antigens to T-cell receptors (TCRs). Class I domains (alpha-1 and alpha-2) typically present endogenous peptides to CD8+ T cells, while Class II domains (alpha-1 and beta-1) present exogenous peptides to CD4+ T cells (Janeway et al., 2001; Rock et al., 2016). These domains form a unique binding cleft that determines the specificity of the immune response, making them central to immune surveillance, pathogen defense, and the recognition of malignant cells (Trowsdale & Knight, 2013). In oncology, these domains are targeted by peptide vaccines and TCR-based therapies, such as Tebentafusp, which recognize specific peptide-HLA complexes to direct T-cell cytotoxicity against tumors (Sahin & Türeci, 2018). Additionally, certain small-molecule drugs can bind within these domains, leading to drug-induced hypersensitivity syndromes by altering the self-peptide repertoire presented to the immune system (Illing et al., 2012). Genetic variations in these domains are also primary drivers of autoimmune disease susceptibility and are the critical factors in determining transplant compatibility.

Other names

MHC peptide-binding grooveHLA antigen-binding cleftMajor Histocompatibility Complex peptide-binding domainsHLA-A/B/C and HLA-DR/DQ/DP binding domains

Therapeutic agents interact with these domains by presenting specific antigens to elicit an immune response, by serving as the recognition site for engineered T-cell receptors and bispecific molecules, or by non-covalently binding within the groove to alter peptide presentation and trigger immune-mediated adverse effects.