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T Cell Receptors . By: Alexander Ko , David Lam, Caddie Sze and Vicky Yee Date: November 4 th , 2013. PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson. What is T Cell Receptor.

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t cell receptors

T Cell Receptors

By: Alexander Ko, David Lam, Caddie Sze and Vicky Yee

Date: November 4th, 2013

PHM142 Fall 2013

Coordinator: Dr. Jeffrey Henderson

Instructor: Dr. David Hampson

what is t cell receptor
What is T Cell Receptor
  • T Cell Receptor are receptors found on T Cells (also called T Lymphocytes)
  • They bind to and recognize antigens that are bound to a MHC molecules (major histocompatibility complex molecules)
  • Source:
  • RusselP, Wolfe S, Hertz P, et al. Biology: Exploring the Diversity of Life1st Edition. Toronto: Nelson Education Ltd, 2010. Print.
generation of t cell receptors
Generation of T-Cell Receptors
  • Occurs in the thymus
  • By mechanism of somatic recombination
  • Most TCRs contain an α-chain and a β-chain
  • Variability arises due to the unique gene sequences in the α-chain and β-chain and the diversity of the junctions between gene sequences
somatic recombination
Somatic Recombination
  • The mechanism of genetic recombination in the early stages of TCR generation
  • The same mechanism for immunoglobulin (Ig) generation
  • Combines 3 types of gene segments:
    • V – Variable
    • D – Diverse
    • J – Joining
major players in somatic recombination
Major players in Somatic Recombination
  • Recombinant Signal Sequences (RSSs)– Nucleotide sequence which attaches to the ends of the gene sequences used for DNA cleavage
  • VDJ Recombinase – Group of enzymes that cleave DNA at the RSSs
  • Terminal deoxynucleotidylTransferase(TdT) – An enzyme that randomly joins gene sequences
mechanism of recombination
Mechanism of Recombination
  • The V, D, & J gene sequences are flanked by Recombinant Signal Sequences (RSSs)
  • Then they are recognized by a group of enzymes known as VDJ recombinase which cleaves the DNA at the RSSs
  • Finally terminal deoxynucleotidyltransferase (TdT) randomly adds nucleotides to the ends
structure of the t cell receptor
Structure of the T Cell Receptor
  • An α and β protein chains
    • carbohydrate side chains
  • A constant region and variable region
  • Disulfides bonds that connect the α and β
  • Trans membrane domain on both the α and β chain
  • A small cytoplasmic tail
  • Figure 3.12 – Structure of the T Cell Receptor
  • Source:
  • http://www.ncbi.nlm.nih.gov/books/NBK27145/
antigen binding site
Antigen Binding Site
  • Only 1 antigen binding site
  • T Cell Receptor combines with a CD3 complex
    • complex acts as a signal transduction mechanism

Figure 3.13The crystal structure of an α:β T-cell receptor resolved at 2.5 Å

Source:

. http://www.ncbi.nlm.nih.gov/books/NBK27145/

recall from undergrad
Recall from undergrad:
  • Kinase (i.e. Lck , Fyn, and Zap 70)– molecules that adds a phosphate
  • Phophatase(i.e. CD45) – molecules that remove phosphates
  • MHC 2 is an antigen presenting cell
t cell receptor signaling1
T-Cell Receptor Signaling
  • The process is low affinity binding and degenerate
  • Not very selective, but at the same time, signal does not persist for a prolonged period of time

What would happen if pathogens bound at relatively high affinities?

therefore
Therefore,
  • Many T-Cell Receptors will recognize the same antigen complex
  • Different types of antigens can bind to the same T-Cell Receptor
  • Produce a large immune response when needed
step 1
Step 1
  • MHC II recognizes that a pathogen is foreign to the body
  • Generates a complex with the foreign material (think of this as now substrate)

Source:

Morrison, L.A., Lukacher, A.E., Braciale, V.L., Fan, D.P. and Braciale, T.J. (1986) Differences in antigen presentation to MHC class I- and MHC Class II-restricted influenza virus-specific cytolytic T-lymphocyte clones. Journal of Experimental Medicine. 163: 903

step 2
Step 2
  • T-Cell Receptor will recognize MHC II molecule with its bound antigen

Source:

"Major Histocompatibility Complex." Protein Data Bank. N.p., Feb. 2005. Web. 15 Oct. 2013.

step 3 activation of kinases
Step 3Activation of Kinases
  • Intracellular Src family tyrosine kinases (Fyn) will be activated by CD45
  • CD45 has a cytosolic tyrosine phosphatase to remove phosphates
step 4 phosphorylation of itams
Step 4Phosphorylation of ITAMS
  • Activated Fyn kinase phosphorylates ITAMS on the cytosolic side of the T-Cell Receptor
  • Phosphorylated ITAMS are a binding site for a secondary tyrosine kinase, Zap 70
step 5 zap 70 binding
Step 5Zap 70 Binding
  • Zap 70 binds to the phosphorylated ITAMs
  • Further amplifies the signal
  • Requires phosphorylation to be activated
step 6 t cell activation
Step 6T-Cell Activation
  • Leads to activation of multiple pathways
  • Induces effector functions
  • Ultimately leads to an immune response in the body against the foreign substance present
t cell receptor tcr deficiency dysfunction
T-Cell Receptor (TCR)Deficiency & Dysfunction
  • Defects that occur during various stages of T-cell maturation can result in deficiencies and dysfunctions of TCRs and its associated molecules
  • Consequences of TCR deficiency and dysfunction varies from increased susceptibility of infections to autoimmunity and severe combined immunodeficiency (SCID)

Source 1: http://harunyahya.com/en/Books/989/the-miracle-of-the-immune/chapter/3768

Source 2: http://arthritis-research.com/content/11/1/202/figure/f1?highres=y

deficiencies of tcr subunits
Deficiencies of TCR subunits
  • Mutation of the T-cell receptor alpha constant (TRAC) gene
    • Defective TCRα chain
    • ↓ expression of TCRαβ T-cells
    • ↑ expression of TCRγδ T-cells
    • Causes autoimmunity and ↑ susceptibility to infections

Defective VDJ recombination of TCR

  • Occurs between the pro-T cell to pre-T cell stage
  • Mutations in the genes encoding for RAG1 and RAG2 enzymes
    • Absence of T cells or decreased TCR functionality
    • Can result in either SCID or Omenn Syndrome

Source: http://www.jle.com/e-docs/00/04/2C/57/article.phtml?fichier=images.htm

defective vdj recombination of tcr
Defective VDJ recombination of TCR
  • Defects in the genes encoding for Artemis, DNA ligase IV, and DNA-protein kinase catalytic subunit (DNA-PKC) involved in DNA repair
  • Causes radiation sensitive SCID (RS-SCID)
    • ↑risk of DNA damage and developing cancer

Defective binding of TCR & MHC

  • MHC Class I deficiency
    • Mutation of TAP1 or TAP2 genes
    • Absence of surface MHC class I molecules
    • Lack of TCRαβ and ↑ susceptibility to infections
  • MHC Class II deficiency
    • Mutation of CIITA, RFXANK, RFX5 or RFXAP genes
    • Lack of expression of MHC class II molecules
    • Severe immunodeficiency
defective tcr signalling
Defective TCR Signalling
  • Mutations of genes encoding for CD3 subunits and CD45
    • Defective CD3 complex/CD45 essential for TCR signalling
    • Causes SCID
  • Defective ZAP-70 protein kinase
    • Absence of CD8 and CD4 T-cells & dysfunctional TCR signalling cascade 1

Adapted from “Janeway’sImmunobiology 8th edition,” by K. Murphy, 2012, Garland Science p. 522

severe combined immunodeficiency scid
Severe Combined Immunodeficiency (SCID)
  • Absence or trivial numbers of functional B-Cells and T-cells
  • Infections are severe and sometimes life-threatening
  • Several forms of SCID
    • i.e. X-linked SCID, “Bubble boy disease”
  • Bone marrow transplant is the most common treatment

Source: http://www.allmovie.com/movie/bubble-boy-v250493

t cell receptors summary
T Cell Receptors Summary
    • T Cell Receptors bind to and recognize antigens bound to a MHC molecules
  • Generation of T Cell Receptors:
    • T-cell Receptors are generated in the thymus by method of somatic recombination
    • Due to the seemingly random recombination, there is lots of variability in cell surface receptors
  • T Cell Receptor Structure:
    • made out of an α and β chain (protein chains) and each chain has a constant and variable region
    • Receptor only has 1 antigen binding site
    • T Cell Receptor combines with a CD3 complex and the complex acts as a signal transduction mechanism
  • T Cell Receptor Signaling (General Pathway):
    • Step 1: Recognition - MHCII recognizes foreign entity in body and generates a complex. T-Cell Receptor will recognize MHCII-complex 
    • Step 2: Activation of Kinases - Src family tyrosine kinases (Fyn) will be activated by cd45, a phosphatase that removes inhibitory phosphates
    • Step 3: Phosphorylation of ITAMS - Activated Fyn kinase phosphorylates ITAMS on cytosolic side of TCR, creating binding sites for Zap70 a secondary tyrosine kinase
    • Step 4: Zap 70 Binding - Binds to phosphorylated ITAMS to further amplify signal (Zap 70 is activated by Lck kinase) to initiate a variety of intracellular responses. 
    • Step 5: Further signalling pathways in cell are then activated to induce appropriate immunological responses towards antigen.
  • T Cell Receptor – Deficiency and Dysfunction:
    • Defects of genes encoding for TCR subunits and its associated molecules can lead to deficient and dysfunctional t-cell receptors
    • Consequences of such defects range from increased risk of infection to autoimmunity and severe combined immunodeficiency
references
References
  • Ballas, Zuhair K. “CD3/T Cell Receptor Complex Disorders Causing Immunodeficiency.” UpToDate. 10 Dec. 2013. Web. 28 Oct. 2013.
  • Clark, Mike. "T-Cell Receptor (TCR)." University of Cambridge. Department of Immunology, n.d. Web. 20 Oct 2013.
  • Huse, Morgan. "The T-Cell Receptor Signalling Network." Cell Science at Glance(2009): n. pag. Web.
  • JanewayCA Jr, Travers P, Walport M, et al. Immunology: The Immune System in Health and Disease 5th Edition. New York: Gardland Science, 2001. NCBI. Web. 28 October 2013. <http://www.ncbi.nlm.nih.gov/books/NBK27145/>.
  • Murphy, Kenneth. Janeway’sImmunobiology 8th Edition. New York: Garland Science, 2012. Print.
  • RusselP, Wolfe S, Hertz P, et al. Biology: Exploring the Diversity of Life1st Edition. Toronto: Nelson Education Ltd, 2010. Print.
  • Severe Combined Immunodeficiency. The SCID Homepage.Calao Designs, 2013. Web. 28 Oct. 2013. <http://www.scid.net/>.
  • T-Cell Receptor (TCR) Overview." T Cell Receptor (TCR) Overview. N.p., n.d. Web. 20 Oct 2013.