Release date: 2017-09-01
The major histocompatibility complex (MHC) is a group of genes closely related to immune function in vertebrates. The MHC and its antigenic systems of different species have different names, but their structural components. , tissue cell distribution and function are similar, such as human major histocompatibility complex called human leukocyte antigen (HLA). HLA antigens are expressed on almost all nucleated cell surfaces. The product of MHC is a key molecule involved in antigen presentation and T cell activation, and plays an important role in the initiation of immune response and immune regulation. It is one of the hot research fields of immunology. HLA has two main functions in immune regulation: binding to inhibitory receptors on the surface of NK cells, inhibiting the activation of NK cells; antigen presentation, in which HLA class I molecules present endogenous antigens, which play a central role in virus clearance. The role of regulation.
Alternative splicing exists in most genes, especially immune-related genes, and studies have found that more than 90% of human genes have alternative splicing. MHC class I molecules (MHC I) undergo different degrees of alternative splicing in different species, resulting in new splice isoforms. At present, the research on alternative splicing of MHC I often stays on the identification of new MHC isoforms, and its function research is scarce. Dr. Dai Zhengxi, a Ph.D. student of the Kunming Institute of Zoology, Chinese Academy of Sciences, discovered and identified a new MHC IA splice isoform (MHC IA-sv1) lacking the exon 4 in rhesus monkeys. MHC I A-sv1 lacks the α3 domain, and the glycosylation pattern and protein degradation rate are significantly different from the full-length MHC IA molecule. MHC IA-sv1 forms a novel heterodimeric structure with MHC IA and does not bind to β2 microglobulin. This heterologous complex significantly inhibits the ubiquitination of the MHC IA protein, thereby promoting its protein stability. However, it is unclear whether humans have this splicing isoform and its function.
In order to investigate the function of HLA splice isoforms in immune regulation and viral immunity, Dr. Zhang Xihe of Kunming Institute of Animals, under the guidance of the instructor Zheng Yongtang, discovered the existence of new splice isoforms in HLA-A11, revealing the fourth exon of HLA. Characterization, expression and function of the deleted isoform (HLA-A11svE4) in the immune system. Studies have shown that HLA-A11svE4 is expressed on the cell surface and does not bind to β2 microglobulin. HLA-A11svE4 not only forms homologs but also forms heterodimers with HLA-A11. It was first discovered functionally that HLA-A11svE4 inhibits the activation of NK cells and the killing of target cells. In addition, HLA-A11svE4 also has the function of presenting antigen. A controlled trial of HIV-infected individuals and the normal population found that HIV-1 significantly up-regulated the expression of HLA-AsvE4. The human immune system removes most viruses but HIV-1 is the exception, and HIV-1 is one of the most difficult to remove viruses. The study proposes a new hypothesis model: HIV-1 protects HIV-1 target cells by up-regulating HLA-A11svE4 to inhibit NK cell activation. Normally, NK cells remain in an inactive state by recognizing HLA molecules on the surface of target cells, while HIV-1 down-regulates HLA molecules, which are activated by the lack of receptors to eliminate HIV-infected target cells. The new model suggests that HIV down-regulates the expression of full-length HLA molecules but up-regulates HLA-AsvE4 expression, whereas HLA-AsvE4 recognizes the inhibitory receptor KIR3DL2 on the surface of NK cells and inhibits NK cell activation, thereby protecting HIV-1. Infected target cells. The study also found that HBV, HSV and CMV in vitro infected cells can also up-regulate the expression of HLA-A11svE4, so this model may be applicable to other viral infections. The findings will provide a new perspective for the research and treatment of diseases such as AIDS.
The research has been highly recognized by international peer review experts, and this pioneering study of HLA isomers opens up new areas of isomer and disease regulation and is an important complement to the classic functions of HLA molecules. The research results were published in the Journal of Immunology, and the project was funded by the National Natural Science Foundation.
Source: Kunming Institute of Animals
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