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How T cells recognize antigen: The T Cell Receptor (TCR)

How T cells recognize antigen: The T Cell Receptor (TCR). Lecture 11, MCB 150 Laurent Coscoy . Identifying the TCR: Why was it so hard to do?. By the early 1980s, much about T cell function was known, but the receptor genes had not been identified

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How T cells recognize antigen: The T Cell Receptor (TCR)

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  1. How T cells recognize antigen:The T Cell Receptor (TCR) Lecture 11, MCB 150 Laurent Coscoy

  2. Identifying the TCR: Why was it so hard to do? • By the early 1980s, much about T cell function was known, but the receptor genes had not been identified • Recall that Ig was purified as soluble myeloma protein • There is no soluble form of T Cell Receptor

  3. Monoclonal antibody approach (Allison and colleagues 1982)

  4. B cell lymphoma Liver cells T cell clones Probed with cDNA clone 1 Probed with cDNA clone 2 Hedrick & Davis strategy: Subtractive cDNA cloning

  5. TCR: Anab heterodimer

  6. A second type of TCR • Hetero dimer of g and d chains (like a and b chains) • Expressed on a rare subset of T cells with fascinating properties (more later)  T cells  T cells CD4 T cells CD8 T cells

  7. Comparison of TCR and BCR (Ig)

  8. T cell receptor loci Analogous to B cell receptor loci

  9. Generation of the T cell receptor

  10. TCR structure

  11. TCR: Peptide/MHC I Interaction Binding groove Peptide CDR3’s Va Vb Variable domains Ca Cb Constant domains

  12. Peptide Binding Grooves of MHC Molecules Class I Class II

  13. Soluble peptide/MHC complexes: a probe to detect specific T cells MHC I Made by genetic engineering; does not exist in nature Ig HC Fc Region

  14. HTLV-I and tropical spastic paraparesis • HTLV-I: • human retrovirus, persistent infection • 20 millions people are infected worldwide • encodes the oncogene Tax • TSP: • progressive inflamatory disease of the CNS • pathogenesis not fully understood

  15. Following Antigen-Specific T Cells CD8

  16. CD4 and CD8: Co-receptors for the TCR

  17. What’s with these “CD” names? • “CD” stands for cluster of differentiation • Many labs generated monoclonal antibodies against cell-surface proteins --> naming of antibodies and their targets was a mess • Conference was called to “clean up” the naming business • Target of monoclonal ab directed against the same surface protein or complex was given a number, as in CD3, CD4, etc.

  18. Co-receptors bind to non-polymorphic regions of MHC I (CD8) or II (CD4)

  19. CD4 and CD8 mark mutually exclusive subsets of mature T cells Flow cytometry of spleen Anti-B220 Anti-CD4 Anti-CD4 & Anti-CD8 Anti-CD3 Anti-gd TCR Anti-CD8

  20. Contrast how B and T cells see antigen B Cell T Cell APC

  21. TCR affinity is quite low

  22. Mysteries in T cell antigen recognition • About 105 copies of each MHC molecule on cell surface • Frequency of any particular Peptide:MHC complex may be as low as 0.01% • How does the TCR sort through all those incorrect complexes and find ones with which to trigger?

  23. Co-receptor and adhesion molecules improve avidity CD2 LFA-3 T cell target cell TCR MHC CD4 or CD8 LFA-1 ICAM-1

  24. Immunological Synapse: A model Red: adhesion Green: Antigen T cell T cell T cell APC APC APC

  25. Immunological “synapse” Peptide-MHC complexes Adhesion molecules (ICAM-1)

  26. The synapse in real-time B-Cell (Peptide-pulsed ) T-Cell 8 minutes in 20 seconds of video

  27. The synapse in real-time

  28. TCR Signal Transduction Why do we care? It helps us understand T cell function It gives us molecular targets for immunotherapy It is an amazing example of biological complexity

  29. Consequences of T cell activation Proliferation Cell cycle entry and cell division Clonal expansion Differentiation Secretion of cytokines (helper cells) Activation of killer functions (cytotoxic cells) Acquisition of effector function Memory Death Important for down-regulation of immune response How is TCR:peptide:MHC binding linked to these events? TCR signaling induces changes in gene expression

  30. Example of T cell activation TCR binds peptide:MHC Induces expression of genes T cells divides many times creating more T cells with the same TCR T cells differentiate and acquire new characteristics

  31. Signal Transduction Transmission of external signals across the membrane and conversion of these signals into intracellular biochemical events Peptide:MHC TCR ? Changes in gene expression

  32. TCR signaling: Big Picture RECEPTOR ? ? ? ? ? ? Alterations in Gene expression ? ? ?

  33. How does the TCR transduce signals with such a little tail?

  34. TCR associates with the CD3 Complex Analogous to the Ig and Ig proteins that associate with BCR on B cells

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