HLA-E

Description

The HLA-E (major histocompatibility complex, class I, E) is a protein-coding gene located on chromosome 6.

HLA class I histocompatibility antigen, alpha chain E (HLA-E) also known as MHC class I antigen E is a protein that in humans is encoded by the HLA-E gene. The human HLA-E is a non-classical MHC class I molecule that is characterized by a limited polymorphism and a lower cell surface expression than its classical paralogues. The functional homolog in mice is called Qa-1b, officially known as H2-T23.

== Structure == Like other MHC class I molecules, HLA-E is a heterodimer consisting of an α heavy chain and a light chain (β-2 microglobulin). The heavy chain is approximately 45 kDa and anchored in the membrane. The HLA-E gene contains 8 exons. Exon one encodes the signal peptide, exons 2 and 3 encode the α1 and α2 domains, which both bind the peptide, exon 4 encodes the α3 domain, exon 5 encodes the transmembrane domain, and exons 6 and 7 encode the cytoplasmic tail.

== Function == HLA-E has a very specialized role in cell recognition by natural killer cells (NK cells). HLA-E binds a restricted subset of peptides derived from signal peptides of classical MHC class I molecules, namely HLA-A, B, C, G. These peptides are released from the membrane of the endoplasmic reticulum (ER) by the signal peptide peptidase and trimmed by the cytosolic proteasome. Upon transport into the ER lumen by the transporter associated with antigen processing (TAP), these peptides bind to a peptide binding groove on the HLA-E molecule.

HLA-E is a non-classical MHC class I molecule involved in immune self-nonself discrimination. It forms a complex with beta-2-microglobulin (B2M) and binds nonamer self-peptides derived from the signal sequence of classical MHC class I molecules (VL9 peptides - VMAPRT[V/L][L/V/I/F]L). This peptide-bound HLA-E-B2M complex primarily functions as a ligand for natural killer (NK) cell inhibitory receptor KLRD1-KLRC1, enabling NK cells to monitor the expression of other MHC class I molecules in healthy cells and to tolerate self. Upon cellular stress, HLA-E preferentially binds signal sequence-derived peptides from stress-induced chaperones, making it no longer recognized by the NK cell inhibitory receptor KLRD1-KLRC1, which results in impaired protection from NK cells. HLA-E also binds signal sequence-derived peptides from non-classical MHC class Ib HLA-G molecules and acts as a ligand for NK cell activating receptor KLRD1-KLRC2, potentially playing a role in the generation and effector functions of adaptive NK cells and in maternal-fetal tolerance during pregnancy. In addition to self-peptides, HLA-E can also bind and present pathogen-derived peptides conformationally similar to VL9 peptides to alpha-beta T cell receptor (TCR) on unconventional CD8-positive cytotoxic T cells, ultimately triggering antimicrobial immune response. HLA-E presents HIV gag peptides (immunodominant KAFSPEVIPMF and subdominant KALGPAATL epitopes) predominantly to CD8-positive T cell clones expressing a TRAV17-containing TCR, triggering HLA-E-restricted T cell responses. HLA-E presents mycobacterial peptides to HLA-E-restricted CD8-positive T cells eliciting both cytotoxic and immunoregulatory functions. {ECO:0000269|PubMed:12461076, ECO:0000269|PubMed:16474394, ECO:0000269|PubMed:17179229, ECO:0000269|PubMed:18083576, ECO:0000269|PubMed:18339401, ECO:0000269|PubMed:20195504, ECO:0000269|PubMed:30087334, ECO:0000269|PubMed:30134159, ECO:0000269|PubMed:34228645, ECO:0000269|PubMed:35705051, ECO:0000269|PubMed:37264229, ECO:0000269|PubMed:9486650, ECO:0000269|PubMed:9754572}

HLA-E is also known as HLA-6.2, QA1.

Associated Diseases

WES Whole Exome Sequencing

Clinical Exome Sequencing