Human leukocyte antigen E (HLA-E) in complex with VL9 or cross-reactive peptides (HLA-E/peptide)

Human leukocyte antigen E (HLA-E) is a non-classical MHC class Ib molecule that plays a pivotal role in the regulation of the innate and adaptive immune systems. It primarily presents a conserved nonamer peptide derived from the leader sequences of other MHC class I molecules, known as VL9 (VMAPRTL[V/I/L]L), which is recognized by the CD94/NKG2 family of receptors on natural killer (NK) cells and a subset of CD8+ T cells (UniProt: P13747). The interaction between the HLA-E/VL9 complex and the inhibitory receptor NKG2A serves as a critical checkpoint that prevents the destruction of healthy "self" cells (PubMed: 30518902). In many malignancies, such as head and neck, colorectal, and lung cancers, HLA-E is overexpressed to exploit this pathway and evade immune detection (PubMed: 31101619). Furthermore, HLA-E can present "cross-reactive" peptides from pathogens like CMV or HIV, or even tumor-associated antigens, which can be recognized by specific T-cell receptors (TCRs), making it a target for novel vaccine and TCR-T cell therapies (PubMed: 26855020). Therapeutic agents like monalizumab are designed to block the HLA-E/NKG2A axis, thereby restoring the anti-tumor activity of NK and T cells in the tumor microenvironment (ClinicalTrials.gov: NCT02643550). Due to its low polymorphism, HLA-E is also being explored as a platform for universal immune therapies that could be applied across diverse patient populations.

Other names

MHC class I antigen EHLA-6.2HLAENon-classical MHC class IbHLA-E/VL9 complexHLA-E/peptide complex

Checkpoint inhibition by blocking the interaction between HLA-E and the inhibitory receptor NKG2A/CD94 on NK cells and CD8+ T cells.