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T-cell Receptors and their importance in Organ Transplant and HIV-mediated Cell Death

T-cell Receptors and their importance in Organ Transplant and HIV-mediated Cell Death. Alex Guan, Henry Vo, Terence Chi Lok Cheung, Nicholas Loy Son Leslie Dan Faculty of Pharmacy, University of Toronto. PHM142 Fall 2014 Instructor: Dr. Jeffrey Henderson. What are T cells?.

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T-cell Receptors and their importance in Organ Transplant and HIV-mediated Cell Death

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  1. T-cell Receptors and their importance in Organ Transplant and HIV-mediated Cell Death Alex Guan, Henry Vo, Terence Chi Lok Cheung, Nicholas Loy Son Leslie Dan Faculty of Pharmacy, University of Toronto PHM142 Fall 2014 Instructor: Dr. Jeffrey Henderson

  2. What are T cells? • Can be referred as T lymphocytes, part of the adaptive immune system2 • From bone marrow -> develop receptors in thymus (gene rearrangement)3 • Two main types: Helper T Cells and Cytotoxic T Cells • Cytotoxic T cells kills infected cells via toxins such as perforins and granzymes that cause the infected cell to undergo apoptosis1 • Helper T cells secrete cytokines that activate cells involved in immune response such as macrophages (phagocytosis). They are also involved in the antibody production process of B cells1

  3. T-cell Receptors • Heterodimer embedded in T cells2 • Two polypeptide chains: α and β (more common) or γ and δ (less common)2 • α polypeptide weighs 40-50kDa, and β weighs 40-45kDa2 • Each polypeptide chain has a variable region and constant region (domains)3 • Variable regions contain different sequences of amino acids which creates different binding sites for a variety of antigens3

  4. T-cell Receptor Structure

  5. How are receptors activated? • Dendritic cells phagocytize invading pathogens and use protease to break the proteins into peptides (antigens)3 • This process is referred to as antigen processing3 • peptides combine with MHC (major histocompatibility complex) and migrate to the surface of dendritic cells where they bind to specific T cell receptor3 • Antigen-presenting cells3

  6. What Are MHCs? • Major Histocompatibility Complex • Cell surface molecules that bind to peptides from processed antigens4 • Can act as antigen presenters to the corresponding T-cell receptors4 • Two classes of MHC: 1 and 24

  7. MHC Binding Restriction • MHC Class 1 bind with intracellular antigenic peptides • May signify that something is wrong with the cell itself (i.e. tumours or bacteria/virally infected cells)4 • These are found on all nucleated cells4 • MHC Class 2 bind with extracellular-origin antigenic peptides • These bind to peptides of pathogens to basically trigger an immune response from certain immune cells by activating them4 • These are found on very specific cells (such as B-cells or macrophages)4 • Cytotoxic T cells (CD8+) are specific for MHC-14 • Helper T cells (CD4+) are specific for MHC-24

  8. CD8 T-cells release cytokines such as IFN-γ and TNF-α to kill the target cell while CD4 T-cells release cytokines for activation4

  9. MHC Binding Restriction • In order to trigger a response, the MHC-peptide complex must4 • Be able to bind perfectly to the TCR4

  10. Background: Receptor mediated entry of HIV into T helper cells • T cells are infected by HIV in a receptor mediated fashion • Gp120 (on HIV) binds to CD4 (on the T cell), inducing a conformational change in gp120 allowing secondary interaction with co-receptor CCXR3 or CCR5.6 • Subsequently, gp41 (on HIV) inserts into the plasma membrane of the T cell, undergoing a conformational change, ultimately fusing the HIV and T cell membranes together, allowing the viral contents to be injected into the cell. 6 Image taken from http://upload.wikimedia.org/wikipedia/commons/c/c7/HIV_attachment.gif

  11. Human Immunodeficiency Virus (HIV) • When infected by HIV, there are two signature events which take place.5 • Depletion of CD4 t-cell • Inflammatory events • Up until 2009, the mechanism of T cell death and the cause of inflammation was unclear. Image taken http://labs.gladstone.ucsf.edu/greene/sites/default/files/imagecache/os_modal_image_500/greene/files/inflammation_cycle.png

  12. Mechanism of CD4 T-helper cell death by HIV-1 virus and possible new treatments • Where does the Inflammation come from? • How is that related to cell death? • Majority of cells die by a process called pyroptosis, a Caspase-1 mediated response.5 • Releases a large amount of inflammatory cytokines.5 • Attraction of other T-cells • “Vicious Cycle” • New drugs: Caspase-1 inhibitors

  13. Organ Transplants: Allogeneic Grafting • In 2013, more than 4,500 Canadians needed an organ transplant7 • Isogeneic Grafting Considerations • ABO blood type compatibility8 • TCR-MHC compatibility9 • Low chances of compatibility, and high rates of rejection9 • Hyperacute Rejection • Acute Rejection • Chronic Rejection Image taken from reference 10

  14. Organ Transplants: Rejection Mechanism • T-Cell-mediated response to MHC 1 • CD8+ cell TCRs recognize the foreign MHC 1on donor cells9 • CD8+ cells induce cytotoxic effects causing donor cells to undergo apoptosis • T-Cell-mediated response to MHC 2 • CD4+ cell TCRs recognize foreign MHC 2 on donor cells9 • CD4+ cells proliferate and secrete cytokines that activate macrophages • Antibody-mediated response to MHC 2 • CD4+ cells communicate with B lymphocytes, which create antibodies against MHC 2 and associated antigens9

  15. T-Cell-mediated response to MHC 1 CD8 CD8 R. CD8+ R. CD8+ MHC 1 TCR TCR Donor APC MHC 2

  16. Antibody and T-Cell-mediated response to MHC 2 Humoral Immune Response CD4 CD4 CD4 R. CD4+ R. CD4+ R. CD4+ TCR TCR MHC 1 TCR Donor APC B Lymphocytes MHC 2 IFN-γ Cytokine Production Proliferation Activated Macrophages

  17. Image taken from reference 9

  18. Summary • T-cells are part of the adaptive immune system, The cells are produced in bone marrow and develop receptors in the thymus. • There exists helper T cells and cytotoxic T cells • The receptor is a heterodimer with two polypeptide chains, usually α and β although γ and δ exists as well • The variable region provides different binding sites for the receptor to bind to different antigens • Dendritic cells break down pathogen to create antigens that bind to MHC in a process called antigen processing • The MHC bound peptide is called antigen presenting cell and it then binds to T cell receptor • MHCs are membrane molecules that act to bind antigen peptides in order to present them to T-cells for a variety of functions • 2 classes: MHC-1/2; MHC-1 can be found on all cells, MHC-2 only on some • CD8 binds to MHC-1, releases cytokines and triggers cell death • CD4 binds to MHC-2, releases cytokines that trigger responses in a variety of different immune cells • In order for a T-cell to bind, the MHC and antigen peptide must be specific • Even if one of the two doesn’t correspond, there will be no reaction • HIV depletes T-helper Cell (CD4+) populations and creates inflammation events • HIV enters the cell in a receptor mediated fashion, using gp120 and gp41 glycoproteins to bind and insert viral contents, respectively. • CD4+ Cell death via pyproptosis releases pro-inflammatory cytokines, attracting other T cells which become infected, propagating the infection as well as chronic inflammation. • New drug prospect: Caspase-1 inhibitors. • It is important to consider both ABO blood type and MHC compatibility when discussing organ transplants. • Incompatibility leads to either Hyperacute (preformed antibodies, within minutes), acute (days-months), or chronic rejection (months-years). • Rejection Mechanisms: T-Cell-mediated (CD8) response to MHC 1,T- Cell-mediated (CD4) response to MHC 2, and Antibody-mediated response to MHC 2 + associated antigen • Immunosuppression drugs + steroids can be used to treat rejection, however none target T-cell receptors

  19. References • Kimball, J.W. (2011, April 5). Cytotoxic T Lymphocytes. Retrieved from http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CTL.html • Owen, J.A., Punt J., Stranford S.A. (2013). Kuby Immunology. New York, NY: W.H. Freeman and Company. • Parham, P. (2009). The immune system. New York, NY: Garland Science, Taylor & Francis Group, LLC. • Murphy, K., Travers, P., Walport, M., & Janeway, C. (2012). Janeway's Immunobiology (8th ed.). New York: Garland Science. • Doitsh, G., Galloway, N. L., Geng, X., Yang, Z., Monroe, K. M., Zepeda, O., ... & Greene, W. C. (2014). Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature, 505(7484), 509-514. • Ray, N., & Doms, R. W. (2006). HIV-1 coreceptors and their inhibitors. In Chemokines and Viral Infection (pp. 97-120). Springer Berlin Heidelberg. • Government of Canada. (2013, December 13). Organ & tissue donation. Retrieved from http://www.healthycanadians.gc.ca/diseases-conditions-maladies-affections/donation-contribution-eng.ph • West, L. J., Karamlou, T., Dipchand, A. I., Pollock-Barziv, S. M., Coles, J. G., & McCrindle, B. W. (2006). Impact on outcomes after listing and transplantation, of a strategy to accept ABO blood group-incompatible donor hearts for neonates and infants. The Journal of Thoracic and Cardiovascular Surgery, 131(2), 455–461 • Kumar, V., Abbas, A., Mitchell, R., & Fausto, N. (2007) Robbins Basic Pathology (8th ed.). Philadelphia: Elsevier - Health Sciences Division. • Welsh, R. M., & Selin, L. K. (2002). No one is naive: the significance of heterologous T-cell immunity. Nature Reviews Immunology 2(6), 417-426.

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