115/9/2015 T Cell Receptor Hugh B. Fackrell Nov 9, 1998

225/9/2015 T Cell Receptor l Assigned Reading l Content Outline l Performance Ojectives –Key terms –Key Concepts l Short Answer Questions

335/9/2015 Assigned Reading l Chapter: 11 pp l Janis Kuby’s Immunology 3rd Ed

445/9/2015 Content Outline l Early Studies l Structure of T cell Receptors l TCR Genes l Cloning l TCR multi gene families l T Cell Receptor Complex l TCR-Peptide-MHC Complex l Associative recognition hypothesis l Formation of ternary complex l Alloreactivity of T Cells

555/9/2015 Early Studies l self MHC restriction l isolation of t cell receptors

665/9/2015 Independent vs Associative Recognition by T cells

775/9/2015

88 Evidence for Altered Self Model

995/9/2015 TCR: Structure l Hetero dimer – 95% Alpha: Beta –2-5% Gamma: Delta l Variable Domains –3 HVR l Constant Domains l Transmembrane region (Tm) –~20 AA l Cytoplasmic Tail (CT) –5-12 amino acids

10 5/9/2015 Structure of T cell Receptors

11 5/9/2015 Cloning TCR Genes DNA subtractive hybridization

12 5/9/2015 TCR Genes

13 5/9/2015 TCR multi gene families: Outline l Variable region rearrangements l TCR DNA rearrangements l Allelic exclusion l Structure of rearranged TCR genes l Generation of TCR diversity

14 5/9/2015 TCR Multigene Families: General l 4 multigene families l one for each chain l Gene rearrangements –Alpha: Gamma - V J exons –Beta: Delta - V D J exons l Chain exclusion

15 5/9/2015 TCR Gene Rearrangement

16 5/9/2015 TCR vs Ig

17 5/9/2015

18 5/9/2015

19 5/9/2015 T Cell Receptor Complex l CD4 & CD8 coreceptors l Accessory membrane molecules

20 5/9/2015 TCR-Peptide-MHC Complex

21 5/9/2015

22 5/9/2015 Associative recognition hypothesis l Formation of ternary complex l Affinity of TCR l Peptide topology

23 5/9/2015 Alloreactivity of T Cells

24 5/9/2015 Performance Objectives

25 5/9/2015 Key Terms l CD2, CD4, CD8, CD28, CD54, CD58, integrins, T cell receptors, l alpha beta TCR, gamma delta TCR, Transcription factor l NF-KB

26 5/9/2015 Key Concepts l Draw the structure of the T Cell Receptor (TCR) l Compare and constrast the structure of TCR with B cell receptor l Draw a diagram of the T cell receptor gene organization

27 5/9/2015 l Describe the stragetgies for diversification of T Cell Receptors l Describe how a T cell Receptor recognizes an antigen l Describe the TCR-Antigen-MHC complex

28 5/9/2015 Short Answer Questions

29 5/9/2015 l Hedrick and Davis used the technique of subtractive hybridization to isolate cDNA clones encoding for the T cell receptor. –Briefly explain the method of subtractive hybridization. –State why this method was so important in the characterization of the TCR.

30 5/9/2015 l What does it mean to say that TCRs belong to the Ig supergene family? l Briefly describe the heterodimeric structure of the TCR. l TCR genes use the same strategies as antibody genes to develop receptor diversity; however, TCR genes do not exhibit somatic hypermutation. Why? l The TCR is closely assoicated with another surface protein complex. What is its name and function?

31 5/9/2015 l Describe the three way complex that occurs during antigenic recognition by T cells. l T cells can react only with protein fragments. –What is this process called? – How does it occur? l Which pathway leads to antigen interaction with MHC-I molecules? l Which pathway leads to interaction with MHC-II molecules?

32 5/9/2015 l What are accessory molecules? –Give some examples. –Briefly discuss how they may be involved in antigen recognition by T cells.