HLA-E is a non-classical MHC class I molecule that exhibits limited polymorphism and lower cell surface expression compared to its classical counterparts. HLA-E plays a unique role in immune responses. It can present antigen epitopes derived from pathogens, tumors, and self-antigens to CD8+ T cells for recognition by their T cell receptors (TCRs), mediating CD8+ T cell responses. HLA-E can interact with inhibitory receptors CD94/NKG2A/C on NK cells and some T cells, regulating their killing activities. Recent research has found that HLA-E-restricted T cells are able to recognize and destroy infected cells, playing a crucial role in the immune response against COVID-19. HLA-E was found to be resistant to inhibition by the virus, even though other classical HLA proteins were suppressed. When HLA-E-restricted T cells recognize the presented antigen fragments, they become activated and release cytotoxic factors to destroy the infected cells.