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The Immunity Evasion of CD8+ T cells in the Epstein Barr-Virus

One of the most important functions of the human body’s immune system is to destroy foreign particles that can harm the body such as bacteria and viruses. Basically, this function of the immune system is carried out by various white blood cells called lymphocytes, which include the T-Cell and the B-Cell.

The B-cell’s principal role is to make antibodies that will help fight against pathogens while the T-Cell plays a major role in cell-mediated immunity, which includes the killing of viruses and tumor cells. However, recent studies have shown that there is a certain virus that has the ability to evade recognition by the body’s immune system and therefore, avoid being eliminated by the cell responsible for killing viruses.

According to the research article, A CD8+ T cell immune evasion protein specific to Epstein-Barr virus and its close relatives in Old World primates, which was authored by Andrew Hislop, Maaike Ressing, Daphne van Leeuwen, Victoria Pudney, Danielle Horst, Danijela Koppers-Lalic, Nathan Croft, Jacques Neefjes, Alan Rickinson, and Emmanuel Wiertz and was published by the Rockefeller University Press, it was shown through an experiment that cells infected by the Epstein-Barr virus (EBV) become less susceptible to the CD8+ T Cell as it moves through the phase of gene expression.

Based on the article, it was discovered that as the EBV-infected cells move through the lytic cycle, which is the type of EBV’s gene expression wherein viral proteins infect human cells to produce virions, are less affected by CD8+ T cell recognition, simultaneous with a decrease in the function of the transporter associated with antigen processing (TAP) and a decrease in the expression of the surface human histocompatibility leukocyte antigen (HLA) I (Hislop et al. , 2007).

The cause of this seemingly evasive action of the EBV-infected cells to CD8+ T cell recognition was due to the presence of a gene, BNLF2a, which efficiently inhibited antigen-specific CD8+ T cell recognition through HLA-A–, HLA-B–, and HLA-C–restricting alleles when it was expressed in target cells in vitro, during the early stage of the lytic cycle (Hislop et al. 2007). In this regard, this paper will discuss in detail the procedure of this experiment and also explain the significance of decrease of the EBV-infected cells’ susceptibility to CD8+ T cell recognition.

In addition, the paper will also review information that are related to the paper and also give a brief historical background on the Epstein-Barr Virus which is the main point of interest. Background and Related Literature In order to fully grasp the essence and results of the experiment, it is necessary to first review related terms and information that are pertinent to the subject. Epstein-Barr Virus The virus belongs to the herpes family, which also includes the Herpes Simplex Virus and the Cytomegalovirus, under the genus lymphocryptovirus (Carter and Saunders, 2007).

It is also called Human Herpes virus 4 which and commonly causes infectious mononucleosis, which is a disease characterized by fever, muscle weakness, enlargement of lymph nodes, and, sore throat It can also cause complications such as meningitis and encephalitis (Nathanson, 2007). Like most viruses, the Epstein-Barr virus infects other cells, particularly, the B-lymphocytes or B Cells, in order to multiply. As it infects the cell, it also passes its genetic information such as its DNA. This process of gene expression can be categorized as lytic or latent (Carter and Saunders, 2007).

In the lytic cycle, the virus penetrates the host cell and releases its genetic material which, in the case of the Epstein-Barr virus, is DNA. This is the phase wherein the infected cell can also be targeted by the immune system. The virus then uses the cell to produce several viral components and the EBV, being a DNA virus, transcribes its DNA into a messenger mRNA (Carter and Saunders, 2007). In addition, the first polypeptide translated eliminates the host DNA. Finally, the several viral components are assembled into complete viruses which produce an enzyme that breaks down the cell wall and allows liquid to enter.

Ultimately, the cell becomes filled with hundreds of viruses and fluid and bursts or lyses, releasing small viruses that can infect other cells (Carter and Saunders, 2007). On the other hand, in the latent cycle, instead of producing small viruses, the virus produces a set of distinct viral proteins. These proteins include the EBNA-leader protein (EBNA-LP), latent membrane proteins (LMP)-1, LMP-2A and LMP-2B, Epstein-Barr nuclear antigen (EBNA)-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, and the Epstein-Barr encoded RNAs (EBERs) (Carter and Saunders, 2007).

These viral proteins ultimately result in the growth transformation and the weakening of the B-cell (Nathanson, 2007). CD8+ T cells mechanism of activation CD8+ T cells or cytotoxic T cells are a sub group of T-Lymphocytes that are capable of killing tumor cells and other cells that are infected with viruses or other pathogens (Roit et al. , 2007). Its main function is to destroy virally-infected cells before it can release a fresh set of viruses. Basically, as discussed before, the virus invades the body’s cell and uses its metabolic processes to produce more viruses.

However, as mentioned before, as the virus inserts its genetic information into the cell it also susceptible to the body’s immune system. This is where the T cell activation begins. The infected cell, due to the degradation caused by the virus, display foreign antigens called peptide fragments of the viral proteins on their surface Major Histocompatibiliy Complex class I (MHC Class I) molecules (Roitt et al. , 2007). These fragments are then presented to the T cell antigen receptor (TcR) of the cytotoxic T cells.

The cytotoxic cells, upon recognition of the foreign antigens, bind to the infected cell and destroy it before it can release a fresh set of viruses that can infect other cells (Roitt et al. , 2007). In short, the CD8+ cells or cytotoxic cells constantly monitor the body’s cell and destroys any cell that express foreign antigens, usually in the form of peptide fragments, in their surface MHC class I molecules. Major Histocompatibility Complex Class I. The Major Histocompatibiliy Complex (MHC) is basically a large area of genomic molecules displayed on cell surfaces that play an important role in the immune system.

It is basically responsible for lymphocyte recognition and “antigen presentation” (Roitt et al. , 2007). The MHC region is divided into three subgroups: MHC class I, MHC class II, and MHC class III (Roitt et al. , 2007). However, since this paper is primarily concerned with the immunity evasion of CD8+ Tcells in the Epstein – Barr virus, only the MHC class I will be discussed in depth. Basically, MHC class I molecules are composed of two polypeptide chains, which are the basic structure and sequence of the proteins’ amino acids.

In the immune system, the MHC class I molecules’ role is to display the foreign antigens on the host cell’s surface so that that they can be recognized by T- Cells, specifically the TcR of the CD8+ cell (Roitt et al. , 2007). Transporter Associated with Processing (TAP) Possibly one of the most important functions of the Major Histocompatibility Complex Class I molecule is to encode dimeric peptide-binding proteins and antigen-processing molecules like the transported associated with processing (TAP) (Roitt et al.

, 2007). Basically the TAP’s role is deliver the peptides into the endoplasmic reticulum where they bind growing MHC Class I molecules which is essential in the activation of CD8+ cells or cytotoxic cells during viral infection (Roitt et al. , 2007). Research Proper and Results discussion Basically, in the experiment, the authors first tested six genes of the Epstein-Barr virus in vitro or outside the body, and tested their ability to inhibit the action of the CD8+ T cell or cytotoxic T cell on them (Hislop et al, 2007).

Among the six genes, only the BNLF2a reduced the activity of the CD8+ T cell, which, as discussed before, kills virally-infected cells before it can release new viruses that can infect other cells. Moreover, in order to determine the mechanism of action of the BNLF2a, which is the gene in question, the authors also examined the activity of gene’s MHC Class I molecule, which displays the foreign antigens on the host cell’s surface so that the CD8+ T cell or cytotoxic cell can recognize them and initiate its usual mechanism of action.

Based on the results, the surface MHC class I molecules of the BNLF2a gene were down-regulated and, as a result, prevented the foreign antigens of the EBV-infected cell from being displayed on the cell’s surface and from being presented to the CD8+ cell (Hislop et al, 2007). Furthermore, the experiment also showed that the BNLF2a gene blocks the peptide transport action of the transport associated with processing (TAP). The authors used a translocation assay to assess the TAP activity in cells that expressed the BNLF2a gene when compared with a control gene.

According to the results, in the cells that expressed the BNLF2a gene, the delivery of the peptides to the budding MCH class I molecules in the Endoplasmic reticulum were severely impaired (Hislop et al, 2007). As a result, the MCH class I molecules were unable to function normally and were unable to present the foreign antigen to the CD8+ T cell or cytotoxic T cell. In addition, since the MCH class I molecules were unable to display the foreign antigens of the EBV gene, the CD8+ T cells were not able to recognize and destroy it Analysis

Basically, based on the results of the experiment, it is can be deduced that the Epstein-Barr Virus as well as the other old world lymphocryptoviruses have acquired a way of evading the CD8+ T Cells’ mechanism of action on viruses as they evolved over the years. This new “evasion strategy” was due to the emergence of a gene, the BNLF2a, which impaired the TAP’s delivery of peptide bonds or the antigenic fragments to the growing MHC Class I molecules and thereby inhibiting the MHC Class I to present these fragments to the CD8+ T cells.

The new evasive technique of the EBV virus has several implications. First, it showed that the EBV and even other viruses can acquire new means of suppressing and counteracting the natural response of the immune system as they evolve. In addition, this finding shows that the EBV, through its BNLF2a gene, can not only prevent its antigenic fragments from being displayed by the MHC Class I molecules but can also ultimately inhibit the action of the CD8+ T cells, which is to destroy a virally infected cell before it can release new viruses that can spread throughout the body and infect other cells.

Moreover, the research implies that although the body’s immune system has natural ways of fighting foreign particles such as bacteria and viruses, these foreign particles, as well as other pathogens, have the potential to evolve and develop new means of inhibiting the various responses of the immune system. In other words, viruses, bacteria, and other pathogens have the capability to avoid being killed by the body’s immune system as they evolve.

In this regard, these developments also imply that researchers in the field of health and sciences should constantly research on viruses as well as other pathogens in order to avoid potential outbreak of diseases and illnesses. Since these foreign particles can constantly change over time, it is essential for those involved in the health and sciences to obtain new information about these foreign particles so that they can develop new cures for the diseases they may cause.

References

Primary reference: Hislop, A. , Ressing, M. , Van Leeuwen, D. , Pudney, V. , Horst, D. , Koppers-Lalic, D. , Croft, N. , Neefjes, J. , Rickinson, A., and Wiertz, E. (2007, August 5). A CD8+ T cell immune evasion protein specific to Epstein-Barr virus and its close relatives in Old World primates. The Journal of Experiment Medicine. The Rockefeller University Press, 204. Retrieved March 26, 2008 from PubMed Central. Secondary references: Burton, D. , Delves, P. , Martin, S. and Roitt, I. (2006). Roitt’s Essential Immunology (Essentials). United Kingdom: Wiley-Blackwell Publishing. Nathanson, N. (2007). Viral Pathogenesis and Immunity. San Diego: Academic Press. Carter, J. and Saunders, V. (2007). Virology: Principles and Applications. Indianapolis: Wiley Publishing.

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