Self-reactive human CD8⁺ T cells restricted by HLA-E mediate immunoregulatory and antiviral functions

HLA-E constitutively presents self VL9 peptides on healthy cells, signaling an intact HLA class I pathway and protecting cells from natural killer cell attack. Beyond this canonical role, HLA-E-restricted CD8⁺ T cells that recognize foreign pathogen peptides have emerged as mediators of immunity in multiple human infections, with orthologous responses conferring unprecedented protection in an HIV vaccine model. However, the poor stability of most pathogen-derived HLA-E ligands raises the possibility that additional modes of HLA-E-restricted recognition remain undiscovered. Here, we establish an alternative paradigm in which HLA-E-restricted CD8+ T cells recognize disease-associated increases in self-VL9/HLA-E rather than foreign antigen. These cells, which we term E-sensors, integrate activating and inhibitory signals to discriminate physiological from pathological levels of HLA-E expression. We demonstrate that E-sensors selectively eliminate highly activated, proliferating immune cells that express high levels of HLA-E, establishing a mechanistically resolved pathway of human CD8+ T cell immunoregulation. E-sensors also recognize pathogen-induced HLA-E upregulation and directly eliminate infected cells without prior pathogen-specific priming, demonstrating immediate immunosurveillance through recognition of increased self. Consistent with this antiviral function, we establish E-sensors as a previously unrecognized component of spontaneous HIV immune control in persons who naturally control infection. Together, our findings establish a pathway of human immunosurveillance and immunoregulation in which CD8⁺ T cells detect pathological increases in a constitutively expressed non-classical HLA class I molecule presenting a conserved self-peptide. This disease-agnostic mechanism of immune recognition has implications across infection, cancer, autoimmune disease, and other pathologies that upregulate HLA-E. Unlike classical HLA class I molecules, the near-monomorphic nature of HLA-E further positions this pathway as an untapped effector axis, warranting investigation as a potential target for immune interventions.