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

Self-reactive CD8+ T cells that are regulated by HLA-E exhibit both immunoregulatory and antiviral capabilities within the human immune system. These cells, dubbed E-sensors, detect elevated levels of self-VL9 peptides presented by HLA-E on healthy cells, rather than foreign antigens. By combining activating and inhibitory signals, E-sensors can discern between normal and abnormal HLA-E expression levels, leading to the elimination of immune cells with high HLA-E expression.

This mechanism enables E-sensors to actively patrol for infected cells, eliminating them without prior pathogen-specific exposure, thus providing immediate immunosurveillance. The discovery of E-sensors as a crucial element in HIV immune control in naturally controlled infections suggests their role in defense against viral diseases.

Moreover, the findings indicate that HLA-E, a non-classical HLA class I molecule, plays a broader and more versatile role in immune recognition, extending beyond classical HLA class I molecules. This pathway of immunosurveillance and immunoregulation holds significant implications for various health conditions, including infection, cancer, autoimmune diseases, and other pathologies involving HLA-E upregulation.

Given the near-monomorphic nature of HLA-E, this immune recognition pathway presents an underexplored target for potential immune interventions in diverse medical contexts.