The Expanding Role of HLA-E in Host Defense: A Target for Broadly Applicable Vaccines and Immunotherapies

Human leukocyte antigen (HLA)-E, a non-classical class I molecule with limited polymorphism, bridges innate and adaptive immunity. Traditionally, the role of HLA-E had been associated with regulating natural killer (NK) cell activity via CD94/NKG2 receptors, by presenting self-peptides derived from the leader sequence of HLA-I. Recent findings reveal its ability to present pathogen-derived peptides to CD8⁺ T cells, eliciting unconventional cytotoxic responses. This review examines the expanding role of HLA-E-restricted T cells in viral and bacterial infections and their capacity to recognize diverse microbial peptides and enhance immune response when classical HLA pathways are impaired. We also highlight key advances in immunotherapy and vaccine development, including CMV-vectored platforms, donor-unrestricted TCR-based strategies, and peptide prediction algorithms. The minimal polymorphism of HLA-E, its resistance to viral immune evasion, and its ability to present conserved pathogen peptides position it as a promising target for universal vaccines and next-generation immunotherapies. Understanding these unconventional roles may pave the way for broadly applicable immunotherapies and vaccines against infectious diseases.