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T cell and Natural Killer cell recognition by Human Cytomegalovirus and Adenovirus.
Natural Killer cells and Cytotoxic T lymphocytes are key cells in the first line of immune response against viruses. Cells display peptide fragments via the MHC class I molecules, the recognition of these peptides act like signals to the innate immune system. Viruses such as Adenovirus and Cytomegalovirus have evolved a variety of mechanisms to mask cellular invasion and cause persistent infections.
Many aspects and steps of antigen presentation are targeted by viral products to inhibit their recognition.
Viruses can up regulate the expression of ligands that activate lymphocytes and also down regulate the expression of MHC class l. NK and CTL activation are distinct ensuring an alternative line of defence when either is inhibited. Introduction The immune system responds to viral infection via effector cells, such as Natural Killer cells (NK cells) and Cytotoxic T lymphocytes (CTL)I , which recognise infected cells.
NK is a lymphocyte that expresses a range of cell surface receptors, this feature differs this cell from most other lymphocytes 1, making it the best adapted to be the first line of defence against infections.
The NK cell surface expresses both activating and inhibitory receptors, which recognise different antigens presented on infected cells. Nucleated cells express peptide fragments of the proteins produced within the cell, on their surface via the MHC class l. Healthy cells present house keeping peptide fragments whereas infected cells present foreign peptides.
These peptide fragments in MHC class I complex are recognised by the T cells containing CD8 surface glycoprotein (so called CTR) activating the CTL.
The NK cell activity is mainly regulated by receptors that are complementary to major histocompatibility complex MHC) class I antigens (peptide fragments), the level of specific activated receptors (activating and inhibitory) will decide whether to target the cell. 2 The MHC class I consists of 2 polypeptides: one membrane-integrated alpha (a) chain that folds to form 3 alpha (a) domains, and integral a non-covalently bound beta-2 microglobulin (?2m) .
Two a domains form the groove on the upper surface of the MHC class I molecule where the peptide fragments bind, to give rise to an antigen presenting MHC class l. The polypeptides fold and assemble into the class I MHC in the Endoplasmic Reticulum (ER) lumen where foreign peptide fragments also assemble. In order for these fragments to get from the cytosol into the ER lumen, the transporter associates with antigen presenting (TAP) is required. TAP is a heterodimer composed of TAP 1 and TAP 2 subunits, forming a pore.
TAP also influences the final stages of class I MHC assembly, for this task to be successfully completed, tapasin is essential. Tapasin ease the links of class I MHC and TAP. Once the class I MHC is correctly loaded it migrates to the exporter site where the molecules are selected and packed into cargo vesicles to be transported to the Golgi pparatus. (Figure 1) Many viruses have evolved various mechanisms to avoid and supress immune responses, in this essay we will talk more specifically about the mechanisms used by Adenovirus (And) and human cytomegalovirus (HCMV).
Explain the underlying principles how cytotoxic T cells (CTL) and NK cells recognize their target cells. Natural Killer cells and Cytotoxic T lymphocytes are white blood cells produced in the bone narrow and are part of the innate immune system. Both cell types induce infected cells to undergo apoptosis before the virus has had the chance to replicate inside the cell. Natural killer cells, as well as cytotoxic T cells, recognise infected cells by their MHC class I proteins 4. All nucleated cells in the human body contain this cell surface molecule, which presents peptide fragments of proteins synthesised inside the cell.
In infected cells, the peptide fragments for antigen presentation are a result of the processing of viral proteins done by the protease proteasome. The CTL recognises the viral peptide fragments presented by MHC class I protein, whereas NK cells monitor the level of MHC class I on the cell surface. Cells presenting a low level of MHC class I proteins are targeted to be killed y the natural killer cells regardless of the peptide fragments it presents. Many viruses have developed mechanisms to suppress the expression of MHC class I on cells that it invades.
By down regulating MHC class l, it inhibits the presentation of viral antigens and these cells are therefore not detected by CTL. The down regulation of MHC class I in infected cells makes them more vulnerable for NK attacks. Natural Killer (NK) cells express a range of receptors that cannot be rearranged. These receptors are activator (such as NKG2D) and inhibitory receptors (such as NKG2A), nd each of these recognise a specific ligand on the surface of infected cells. The balance between the activation of activating receptors and inhibitory receptors regulates the activation of (NK) cells.
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