HLA-E

Official Full Name

major histocompatibility complex, class I, E

Organism

Homo sapiens

GeneID

3133

Background

HLA-E belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-E binds a restricted subset of peptides derived from the leader peptides of other class I molecules. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exons 6 and 7 encode the cytoplasmic tail. [provided by RefSeq, Jul 2008]

Synonyms

QA1; HLA-6.2;

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Detailed Information

Major histocompatibility complex (MHC) class I molecules have important functions in both the innate immune system and the adaptive immune system by delivering peptides from intracellular proteins to lymphocytes and acting as ligands for natural killer (NK) cell receptors. The human leukocyte antigen-E (HLA-E), also known as MHC class I antigen, is a protein encoded by the human HLA-E gene. Human HLA-E is a non-classical MHC class I molecule characterized by HLA-E expressed in almost every healthy cell in the body. HLA-E has a limited polymorphism compared to highly polymorphic HLA class I molecules, and two dominant protein variants have been identified to date. The molecular structure of HLA-E is very similar to that of class I, consisting of a heavy chain composed of an extracellular domain of α1-3, a transmembrane domain, and a protein intracellular domain. Like the classical HLA class of molecules, the heavy chain of HLA-E molecular pairs with invariant light chains, namely β2-microglobulin (β2-m). Under steady state conditions, HLA-E binds to a peptide in an intracellular protein, such as a peptide in the leader sequence of a classical HLA class I molecule, a polypeptide in heat shock protein 60 (Hsp 60). In addition, HLA-E can also bind to peptides from intracellular pathogens such as cytomegalovirus (CMV) (UL40), hepatitis C (HCV), EB virus (EBV), human immunodeficiency virus (HIV), mycoplasma, and salmonella. (GroEL).

Effect on cellular immune response

The effects of changes in HLA-E and HLA-E expression levels on cellular immune responses are complex because HLA-E interacts with NK cells and CD8 T cells to activate and inhibit receptors, depending on the recipient and responder cells. The involvement of HLA-E may result in immune activation or inhibition. Binding of HLA-E to CD 94/NKG2A provides an inhibitory signal to NK cells, while interaction of HLA-E with CD 94/NKG2C transmits an activation signal to NK cells. Both receptors recognize overlapping epitopes of HLA-E, and the binding ratio of HLA-E to NKG2A has a higher affinity than NKG2C. Therefore, the interaction of NK cells with HLA-E mainly leads to inhibition of NK cells. Peripheral blood T cells express NK receptors (NKRs), such as CD 94/NKG 2, which allow these T cells (primarily CD45RO CD8 T cells) to recognize HLA-E. The NKG 2 subunit of CD8 T cells binds to the Qa-1 (mouse HLA-E) peptide complex in the same manner as NK cells. The Qa-1 peptide complex interacts with the CD 94/NKG2A receptor on CD8 T cells to transmit an inhibitory signal, and the Qa-1 peptide complex binds to CD 94/NKG2C expressed on CD8 T cells, resulting in CD8 T cell activation. In addition, HLA-E-restricted cytotoxic CD8 T cells can also interact with HLA-E peptide complexes via their αβ T cell receptor (αβtcr). HLA-E restricted CD8 T cells act as a regulatory system for the peripheral immune system, maintaining self-tolerance by distinguishing between self and non-self.

Effects in allogeneic hematopoietic stem cell transplantation

Allogeneic stem cell transplantation (allo-SCT) is an important treatment for hematological malignancies. Allo-SCT may be an effective treatment depending on the underlying disease, but it may also have serious complications. For example, the response of T cells from donors to the patient's cell response to graft-versus-host disease (GvHD),) host-versus-graft (HVG), recurrence of the disease, transplantation related mortalities (TRMs). HLA has a high degree of polymorphism and plays an important role in antigen presentation, which is an important factor affecting the results of allo-SCT. Studies have shown that in mice, CD8 T cells from non-transgenic mice reject transplanted HLA-E*01:03 skin grafts from mice. In mixed lymphocyte reaction (MLR), HLA-E induces proliferation of human TCRαβ xenogenic CD8 T cells with the ability to kill target cells expressing HLA-E in the HLA I class leader peptide or viral peptide complex. Finally, HLA-E can act through bystander cells (such as endothelial cells), which once activated, attract and activate receptor T cells, leading to graft rejection.

The impact of HLA-E in cancer

Since CD8 T cells and NK cells control tumor growth, they have an important influence on the immune evasion of tumor variant development. The lack of HLA-I allows tumor cells to escape the cytotoxicity of T cells, while the presence of HLA-E protects them from the cytotoxicity of NKG2A expressed by most NK cells. Many tumors have been observed to maintain HLA-E expression, even in the absence of classical HLA-like molecules, suggesting that HLA-E has a major immunosuppressive effect in anti-tumor immunity. Recently, CD 94/NKG2A and αβTCR-positive CD8 T cells were found to be enriched in gynecological and colorectal cancer biopsies. HLA-E may also occur in a soluble form, possibly after cleavage of the protease from the cell membrane, and these soluble HLA-E molecules have immunomodulatory activity. Studies have shown that there is shedding soluble HLA-E in melanoma cells. Soluble HLA-E was detected in 98 multi-source cell culture supernatants, and soluble HLA-E was detected in the serum of melanoma patients compared with the healthy control group (65 cases). In addition, it is also increased in the serum of patients with neuroblastoma.

References:

Wieten L, Mahaweni N M, Voorter C E, et al. Clinical and immunological significance of HLA-E in stem cell transplantation and cancer [J]. Tissue Antigens, 2016, 84(6):523-535.
King A, Allan D S, Bowen M, et al. HLA-E is expressed on trophoblast and interacts with CD94/NKG2 receptors on decidual NK cells [J]. European Journal of Immunology, 2015, 30(6):1623-1631.
Llano M, Lee N, Navarro F, et al. HLA-E-bound peptides influence recognition by inhibitory and triggering CD94/NKG2 receptors: preferential response to an HLA-G-derived nonamer [J]. European Journal of Immunology, 2015, 28(9):2854-2863.
Zeestraten E C, Reimers M S, Saadatmand S, et al. Combined analysis of HLA class I, HLA-E and HLA-G predicts prognosis in colon cancer patients [J]. British Journal of Cancer, 2014, 110(2):459.
Pietra G, Romagnani C, Falco M, et al. The analysis of the natural killer-like activity of human cytolytic T lymphocytes revealed HLA-E as a novel target for TCR alpha/beta-mediated recognition [J]. European Journal of Immunology, 2015, 31(12):3687-3693.

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