t cell receptor

1. The University of Zambia
T Cell Receptor & Ig Supergene Family (I)
Department of Biomedical Sciences
Immunology
BMS 3325
Lecturer: Chris_Chisanga
07/06/2018

2. Goals/Objectives for today:
 Explain the structure of the MHC proteins and how
peptide antigen binds to the peptide groove
 Define the main differences between TCR
rearrangement and antigen recognition and BCR
rearrangement and antigen recognition
 Conceptualize and describe the structural properties
of T cell receptor binding to MHC molecules

3. T Cells Recognize Antigen Displayed on
the Surface of Cells
• B cells and Abs recognize pathogens and toxic proteins in the
extra cellular spaces
• In contrast, T cells recognize antigen fragments of pathogens
that have infected cells or been taken up by endocytosis in
conjunction with host cell proteins. Examples: viruses & bacteria
• Infected cells display bits of antigen (peptides) within special
host glycoproteins called MHC molecules = Major
Histocompatibility Complex
MHC Molecules = encoded in a large cluster of genes identified because
of their importance in the immune response against transplanted
tissues
• The TCR structure is similar to the Fab (fragment of Ab)
molecule, but exists in the membrane of the T cell

4. The T Cell Receptor

5. Similarities and Differences Between TCRs and
Immunoglobulins
1. Similarities
2. Differences
Both receptor types are composed of 2
different peptide chains and have variable
regions for binding antigen
Both receptor types have constant regions
and hinge regions
TCRs are membrane-bound and contain
only a single antigen binding site
TCRs have cytoplasmic domains
Transmembrane domain

6. TCR and Ig Recognize Ag Differently
• TCR responds to short amino acid sequences, contiguous,
internal, needs to be unfolded and processed
• Abs bind to intact antigen, typically surface proteins, known as
conformational epitopes
Ab binding sites on
HEL
Peptide fragments recognized by
TCR
Peptides corresponding to two T-cell epitopes of lysozyme
Epitopes for 3 Abs are shown in different colors on the
surface of hen egg-white lysozyme (HEL)

7. Antigen recognition by B cells involves the direct
binding of Immunoglobulin to the intact antigen
In contrast, the epitopes recognized by T-cell
receptors need not lie on the surface of the molecule,
because the T cell receptor recognizes not the
antigenic protein itself but a peptide fragment of the
protein
For a peptide residue to be accessible to the T-cell
receptor, the protein must be unfolded and processed

8. TCRs DO NOT Bind Peptide Fragments
Directly!!
• The TCR responds to short amino acid sequences, contiguous,
internal, needs to be unfolded and processed
Free floating peptide
not recognized
MHC

9. Critical Difference b/w B and T Cell
Receptors is the Recognition of Antigen
APC

10. Class I and Class II MHC Molecules are
Structurally Different
MHC class II molecule
Consists of 2 transmembrane
glycoprotein chains
MHC class I molecule
Consists of 1 transmembrane
glycoprotein chain

11. MHC Molecules Bind Peptides Within the
Cleft
 Peptides are bound tightly within the cleft, this stabilizes the
MHC
moleculeClass I MHC Class II MHC
Ends
are
tightly
bound
Ends
are
not
bound
as
tightly

12. The TCR Aligns Diagonally Over the
Peptide and Peptide Binding Cleft
• TCR interact with compound ligand and
makes contact with both MHC and the
peptide

13. Co-Receptors Help Stabilize the TCR MHC
Complex and Allow Effective Activation
T cells are characterized by function and distinguished by their cell
surface receptors—CD8 is expressed on cytotoxic T cells and
interacts with MHC Class I while CD4 is expressed on T cells that
activate other cells and interacts with MHC Class II

14. MHC Molecules are Differentially
Expressed on Host Cells
Differential distribution
reflects different
functions of T cells that
recognize them
Class I: CD8 cytolytic cells
Usually present peptides
from infected cells…class
I expression is on all cells
Class II: CD4 helper T
cells
help to activate other
immune cells so class II is
predominantly expressed
on immune cells

15. T Cell Receptor Gene Rearrangement
• T cell receptors and B cell receptors use similar
mechanisms to generate diversity
TCR alpha chain

16. For the TCRα-chain (Upper part of Figure)
 A Vα gene segment rearranges to a Jα
gene segment to create a functional V-
region exon
 Transcription and splicing of the VJα
exon to Cα generates the mRNA that is
translated to yield the T cell receptor α-
chain protein

17. For the TCR β-Chain (Lower part):
 Like the Ig H-chain, the heavy chain, the
variable domain is encoded in 3 gene
segments, Vβ, Dβ and Jβ.
 Rearrangement of these gene segments
generates a functional VDJβV-region exon
that is transcribed and spliced to join Cβ;
 The resulting mRNA is translated to yield the T-cell
receptor β chain
The α and β chains pair soon after their synthesis to yield the
α:β T-receptor heterodimer

18. T Cell Receptor Rearrangement
• TCR alpha chains are similar in genetic makeup as
Light chains, TCR beta chains similar to Heavy chains
TCR alpha chain
TCR beta chain
V-J recombination
VDJ recombination

19. T Cell Receptor Loci Also Contain RSS and
follow the 12/23 Rule
 RSS (Recombinational signal sequences) are recognized by
the same enzymes in B and T Cells
 DNA circles resulting from gene rearrangement in T cells are
called TRECs (T-cell receptor excision circles) and are used as
markers for T cells that have recently emigrated from the
thymus
 T-cell receptor gene segments are flanked by 12-bp spacer and 23-bp RSS that are
homologous to those flanking immunoglobulin gene segments. Thus joining gene
segments almost always follows the 12/23 rule

20. Comparison of Ig and TCR Receptor
Diversity
Combinatorial diversity
**

21. Comparison of Ig and TCR Receptor
Diversity
• Diversity in TCR is attributable mostly to
combinatorial and junctional diversity
• The TCRa locus has so many more J regions (than Ig
locus) that variability generated in this region is large!
• The third hypervariable regions or CDR3 of the TCR a
and b chains (where the D and J segments combine)
form the center of the Ag binding site

22. Va to Ja Rearrangement Deletes the TCRd
Locus
When any V region in
the Va/Vd region
rearranges to any one
of the Ja segments,
the intervening region
and the entire Vd
locus is deleted

23. gd T Cells Comprise a Minor T Cell Subset
Pre-TCR complex is
made up of a
successful b chain
rearrangement
and a surrogate pre
TCR a chain (pTa)
If a complete g:d
chain is formed first,
b chain
rearrangement is
shut off

24. Comparison of Ig and TCR Changes During
Development
T and B cell gene rearrangement share many common
themes

25. Summary
• Antigen recognition receptors belong to the Ig superfamily-B
cells and T cells use structurally similar, but different receptors
• While B cells recognize whole proteins in extracellular spaces, T
cells recognize bits of protein fragments that are bound to
glycoproteins in the host cell surface TCR are membrane bound
Ag receptors
• MHC molecules consist of Ig like domains and alpha helices that
form a peptide binding cleft
• Class I binds peptides 8-10 aa long, with anchor residues toward
the ends of the peptides—also peptide binding groove is more
closed at the end (than class II)
• Class II binds longer peptides that have anchor residues in the
middle of the peptide, the peptide binding groove is more open on
the ends

26. Summary II
• TCR must bind MHC molecule and peptide combination—
polymorphism of MHC allows for many different peptides binding
to many different MHC molecules results in T cells being able to
recognize peptides from almost all pathogens
• TCR:MHC interaction is stabilized by co-receptors, CD4 for class II
and CD8 for class I help to efficiently activate T cells
• Class I and Class II are differentially expressed on host cells
• TCR undergoes same somatic recombination as BCR, alpha chain
similar to L chain, beta chain similar to H
• More diversity in the TCR repertoire due to number of J regions
• g/d T cells make up a small proportion of T cells: g, d and b all
rearrange simultaneously