HLA class I histocompatibility antigen, alpha chain E (HLA-E) (HLA-E)

HLA class I histocompatibility antigen, alpha chain E (HLA-E) is a non-classical MHC class I molecule (MHC class Ib) that plays a pivotal role in modulating both innate and adaptive immune responses [5, 14]. Unlike classical MHC class I molecules, HLA-E exhibits very limited polymorphism and primarily presents peptides derived from the leader sequences of other HLA class I molecules, such as HLA-A, -B, -C, and -G [6, 16]. This presentation serves as a "health signal" to the immune system; when HLA-E is recognized by the inhibitory receptor CD94/NKG2A on natural killer (NK) cells and CD8+ T cells, it suppresses their cytotoxic activity, thereby protecting healthy cells from auto-aggression [1, 20]. In the context of malignancy, many tumors overexpress HLA-E to exploit this inhibitory pathway, effectively creating an immune checkpoint that shields cancer cells from destruction by NK and T cells [3, 19]. Therapeutic strategies targeting the HLA-E/NKG2A axis, including the monoclonal antibody monalizumab (which blocks NKG2A) and direct HLA-E-targeting antibodies like 3H4 or TFL-033, aim to disrupt this suppression and restore anti-tumor immunity [1, 12]. Additionally, HLA-E can present pathogen-derived peptides to unconventional T cells, making it a significant target for research into vaccines and therapies for infectious diseases such as HIV, tuberculosis, and COVID-19 [11, 14, 21].

Other names

MHC class I antigen EHLA-6.2Non-classical MHC class I antigenMHC class Ib antigenHLAEQA1Major histocompatibility complex, class I, E

Blockade of the NKG2A/HLA-E inhibitory checkpoint axis to restore NK and T cell-mediated anti-tumor immunity; direct targeting of peptide-HLA-E complexes for cell-mediated killing; indirect downregulation of surface HLA-E expression.