MBI - 414 Immunology Principles
MBI - 415 Immunology Principles and Practice

T Cell Receptors (TCR)

• T cells rearrange their surface receptor gene segments as they mature
  • Receptor genes are generated as a result of this rearrangement
    • One VDJ gene is generated for beta chain
    • One VJ gene is generated for alpha chain
  • Transcription of these genes allows formation of receptor molecules with a single combining site specificity that is able to interact with a fragment of an antigenic molecule in a highly specific manner
• T cell receptors (TCRs) on their surface "display" the receptor combining site a mature T cell can make, thus allowing them to function in T cell-mediated responses (MHC-Ag-TCR interaction ... in motion)
  • TCRs are NOT secreted by T cells . . . instead . . .
  • T cell proliferation, differentiation and cytokine production result from their specific interaction with antigen fragments via their TCRs, which have two components:
    • TCR-alpha/TCR-beta heterodimers (in pairs)
      • Variable domains containing three hypervariable regions, also known as complementarity-determining regions (CDRs) comprise the N-terminal domains of both TCR-alpha and TCR-beta chains
        • CDRs in the variable domains of TCR-alpha and TCR-beta bind antigen fragments
        • antigen fragments must be bound to MHC molecules on antigen presenting cell (APC) surfaces to be recognized by TCR
      • Constant domains comprise the membrane-proximal domains of TCR-alpha and TCR-beta
        • transmembrane segments (stretches of ~20 hydrophobic amino acids) near the C-terminal end of the both constant domains anchor them to T cell cytoplasmic membranes
        • cytoplasmic tails are nearly nonexistent at the C-terminal ends of these polypeptides, so they are incapable of initiating signal transduction events, even though their N-terminal ends bind antigenic fragments
        • http://www.path.cam.ac.uk/~mrc7/functions/mhc_tcr1.html
    • CD3 must be coexpressed with the alpha/beta heterodimers
      • several polypeptides comprise CD3
        • gamma
        • delta
        • epsilon (in pairs)
        • zeta (these disulfide-linked dimers can be replaced by eta dimers, but zeta is the predominant molecule expressed in CD3)
      • charge-based (electrostatic) interactions link CD3 with the constant regions of alpha/beta herterodimers
      • Zeta and epsilon both have cytoplasmic domains with ITAMs (Immunoreceptor Tyrosine-based Activation Motifs)
        • zeta has three ITAMs (thus it initiates most of the signal transduction)
        • epsilon has one ITAM
      • TCR interaction with antigen fragments bound to MHC molecules on APCs initiates ITAM phosporylation by cytoplasmic protein kinases in T cells
      • ITAMs phosphorylation generates a molecular "signal" that is transmitted to the T cell nucleus via an intracellular signal transduction pathway
  • Clonal selection of T cells is based on recruitment of individual T cells, via their ability to specifically interact with an antigenic fragment, into proliferating populations of T cells that eventually differentiates into:
    • helper T (Th) cells, which actively produce and secrete cytokines
    • cytotoxic T cells (CTLs), which kill abnormal (virus-infected, tumor or graft) cells
    • T memory cells (either Th or CTL), which represent expanded populations of T cells able to respond to the inducing antigenic determinant