HLA-E and HLA-E-bound peptides: recognition by subsets of NK and T cells

Curr Pharm Des. 2009;15(28):3336-44. doi: 10.2174/138161209789105207.


In humans, major histocompatibility complex (MHC) class I molecules comprise the classical (class Ia) human leukocyte antigens (HLA)-A, -B, and -C, and the non-classical (class Ib) HLA-E, -F, -G and -H (HFE) molecules. The best-characterized MHC class Ib molecule is HLA-E. HLA-E was first described as a non-polymorphic ligand of the CD94/NKG2 receptors expressed mainly by natural killer (NK) cells and its role was thus confined to the regulation of NK cell function. Therefore, interaction of HLA-E with the CD94/NKG2 receptors can result in either inhibition or activation of NK cells, depending on the peptide presented and on the NKG2 receptor CD94 is associated with. Thus, CD94/NKG2A functions as an inhibitory receptor, whereas CD94/NKG2C functions as an activating receptor. However, recent evidences obtained by our group and others indicated that HLA-E represents a novel restriction element for ab T-cell receptor (TCR)-mediated recognition. Although HLA-E displays a selective preference for nonameric peptides derived from the leader sequences of various HLA class I alleles, several reports showed that it can also present "non-canonical" peptides derived from both stress-related and pathogen-associated proteins. Because HLA-E displays binding specificity for innate CD94/NKG2 receptors but also has the features of an antigen-presenting molecule--including the ability to be recognized by ab T cells--it does appear that this MHC class Ib molecule plays an important role in both natural and acquired immune responses.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • HLA Antigens / chemistry*
  • Histocompatibility Antigens Class I / chemistry*
  • Humans
  • Killer Cells, Natural / chemistry*
  • Killer Cells, Natural / immunology
  • NK Cell Lectin-Like Receptor Subfamily C / genetics
  • NK Cell Lectin-Like Receptor Subfamily D / genetics
  • Peptides / chemistry*
  • Protein Binding
  • T-Lymphocytes / chemistry*
  • T-Lymphocytes / immunology


  • HLA Antigens
  • HLA-E antigen
  • Histocompatibility Antigens Class I
  • NK Cell Lectin-Like Receptor Subfamily C
  • NK Cell Lectin-Like Receptor Subfamily D
  • Peptides