Chapter 9 T-Cell Receptor. Self-MHC Restriction of the TCR

Chapter 9 T-Cell Receptor

Self-MHC Restriction of the TCR

Structure of TCR

Structural Similarity between TCR and mIgM

Resembling Fab?

Organization and Rearrangement of TCR Genes

Identifying and Cloning the TCR Genes (Hedrick and Davis, 1984)

- TCR mRNA represents a minor fraction of the total cell mRNA.

Well-thought-out assumptions of TCR Genes : 1. mRNAs are associated with membrane-bound polyribosomes rather than with free cytoplasmic ribosomes. 2. mRNAs are only expressed in T, but not in B cells. subtractive hybridization (98% of the genes expressed in T and B cells are the same)

3. DNA is rearranged in mature T cells.

~ 2% of total cDNA

Germ-line Organization of the Mouse TCR -, -, -, and -chain Gene Segments

Gene Rearrangements That Yield aFunctional Gene Encoding the TCR

The C region of TCR is much simpler than the C region of Ig genes:

- TCR is expressed only in a membrane-bound form; thus, no differential RNA processing is required to produce membrane and secreted form.

- TCR has only a single C gene segment and TCRhas two C gene segments.

- No known functional differences exist in C regions.

- Mechanisms of V-region rearrangements of TCR genes are very similar to those of Ig genes.

- Although B cells and T cells use very similar mechanisms for V-region gene rearrangements, the Ig genes are not rearranged in T cells and the TCR genes are not rearranged in B cells.

- Presumably, the recombinase enzyme system is regulated in each cell lineage, so that only rearrangement of the correct receptor DNA occurs.

- A region within the chain 3’ end enhancer can suppress the rearrangement of -chain genes in T cells.

Domains and CDRs of -TCR

Generation of TCR Diversity

TCR Ig

The location of one-turn (12-bp) and two-turn (23-bp) recognition Signal sequences in TCR - and -chain

DNA differs from that in Ig H-chain DNA

Or V-D-D-D-J

Generate considerable additional diversity in TCR genes.

TCR Ig

TCR Ig

T-Cell Receptor Complex: TCR-CD3

or

(immunoreceptor tyrosine-based activation motif)

B-cell Receptor

ITAM

T-Cell Accessory Membrane Molecules

CD4 and CD8 Coreceptors

55-kDa

30-38 kDa each chain

1

2

Interaction of CD8 Coreceptor with TCR and Class I MHC Molecule

Interaction of CD4 Coreceptor with TCR and Class II MHC Molecule

CD4 Interacts with a Dimer of Class II MHC Molecules

A Lattice-type Structure formed by Interaction of CD4 and Class II MHC

Affinity Constants for Various Biological Systems

Interactions between TCR/Peptide-MHCand Accessory Molecules/Ligands

HLA-A2

HTLV-1 tax peptide

Interaction between TCR and HLA-A2 with bound HTLV-I Tax Peptide

TCR

CDR1 & CDR2 of V

CDR3 of V

peptide

H-2Kb

CDR1 & CDR2 of V

CDR3 of V

Ternary Complex of TCR Bound to H-2Kb and Peptide

MHC Molecule Viewed from Above

TCR-V

TCR-V

Peptide

Alloreactivity of T Cells

The End