Clinical and immunological significance of HLA-E in stem cell transplantation and cancer

Human leukocyte antigen-E (HLA-E) is a nonclassical HLA class I molecule that canonically binds peptides derived from the leader sequence of classical HLA class I. HLA-E can also bind peptides from stress protein [e.g. heat shock protein 60 (Hsp60)] and pathogens, illustrating the importance of HLA-E for anti-viral and anti-tumor immunity. Like classical HLA class I molecules, HLA-E is ubiquitously expressed, however, it is characterized by only a very limited sequence variability and two dominant protein forms have been described (HLA-E*01:01 and HLA-E*01:03). HLA-E influences both the innate and the adaptive arms of the immune system by the engagement of inhibitory (e.g. NKG2A) and activating receptors [e.g. αβ T cell receptor (αβTCR) or NKG2C] on NK cells and CD8 T cells. The effects of HLA-E on the cellular immune response are therefore complex and not completely understood yet. Here, we aim to provide an overview of the immunological and clinical relevance of HLA-E and HLA-E polymorphism in stem cell transplantation and in cancer. We review novel insights in the mechanism via which HLA-E expression levels are controlled and how the cellular immune response in transplantation and cancer is influenced by HLA-E.