Transcript T Cell Receptor (TCR)

T Cell Receptor (TCR) & MHC
Complexes-Antigen Presentation
• Pin Ling (凌 斌), Ph.D.
ext 5632; [email protected]
• References:
1. Abbas, A, K. et.al, Cellular and Molecular
Immunology (6th ed., 2007), Chapter 5-7
2. Male D., J. Brostoff, D. B Roth, and I. Roitt
Immunology (7th ed., 2006), Chapter 5 & 7
Question
What are the mechanisms to generate
Ab diversity?
Ans: 1. VDJ gene recombination -
2. Somatic hypermutation -
=> V regions => Ag binding
3. Isotype switching => Fc portion => Effector function
Outline
• Structures & Features of T-cell
antigen receptor (TCR)
• Structures & Features of Major
Histocompatibility Complex (MHC)
• Antigen Presentation to T cells
• Summary & Question
Antibody, TCR & MHC
Key Concepts in T-cell Receptor (TCR)
1. T-cell antigen receptor (TCR) is similar to the F(ab) of
Ab but only located on the surface of T cells
=> No secreted form
=> Two major types: ab TCR and gd TCR
2. TCR functions to recognize Ag peptide and then to
activate T cells => Adaptive immunity
3. Ag recognition by ab TCR requires Ag presented by
Major Histocompatibility Complex (MHC).
=> consider both Ag peptide & MHC
=> Cell-Cell interaction
4. The Ag-binding site region of the TCR is formed by the
Va and Vb regions.
Similarities & Differences between
T-cell Receptor (TCR) and Ab
The Structure of T-cell Receptor (TCR)
T-cell Receptor (TCR) vs. Ab
Binding of a TCR to a peptide-MHC
complex
Front
Side
TCR & Accessory
Molecules
Accessory Molecules
-Help T cells in response
to a specific Ag
1. CD3 (e, g, d ) and z chains :
associates w/ TCR =>
intracellular signaling
transduction
2. CD4/CD8: CD4  MHC-II
CD8  MHC-I
3. CD28: a co-stimulatory
receptor
4. Integrin: Adhesion &
co-stimulation
The TCR/CD3 Complex
TCR/CD3 Complex:
1. TCRab dimer +
multiple CD3 dimers
- CD3eg dimer
- CD3ed dimer
- CD3zz dimer
2. The ITAM motif on
CD3
=> Signaling
Transduction
TCR/CD3 Complex vs BCR/Igab Complex
Interaction between innate and
& adaptive immunity
1. Innate immunity => Ag presentation (by Dendritic cells)
2. Adaptive immunity => Ag recognition (by T & B lymphocytes)
Interactions of Accessory molecules
between T cells & APCs
Outline
• Structures & Features of T-cell
antigen receptor (TCR)
• Structures & Features of Major
Histocompatibility Complex (MHC)
• Antigen presentation to T cells
• Summary & Question
Key Concepts in Major
Histocompatibility Complex (MHC)
1. Ag presentation to TCR is mediated by Two classes of MHC
molecules.
- Class-I MHC => peptides from cytosolic (intracellular)
proteins => CD8 T cells
- Class-II MHC => peptides from extracellular (exogenous)
proteins from phagocytosis => CD4 T cells
2. In humans, the MHC is also called as the HLA (Human
Leukocyte Antigen).
3. MHC genes are the most polymorphic genes present in the genome
and co-dominantly expressed in each individual.
4. MHC molecules express on the cellular surfaces of only in
presence of Ag-peptides.
Class-I => all nucleated cells
Class-II => APCs (DC, Macrophages & B cells)
TCR-Ag w/ Histocompatibility
Complex (MHC)
The Discovery of Major
Histocompatibility Complex (MHC)
Histocompatibility genes: George Snell in 1940s
=> tumors or tissues => same strain, OK
=> foreign strains, No
For their work leading
to the discoveries of
MHC (mouse) and HLA
(human).
- Immune recognition
=> The foundation of
adaptive immunity
- Transplantation
Schematic maps of human &
mouse MHC loci
Class-I vs. Class-II MHC molecule
Structure of Class-I MHC molecule
a1a2 domains are
polymorphic and form the
peptide-binding cleft.
a3 domain is conserved
among all MHC class-I, and
folds into an Ig domain for
CD8 binding.
Structure of Class-II MHC molecule
a1b1 domains are
polymorphic and form the
peptide-binding cleft.
b2 domain is conserved
among all MHC class-II,
and folds into an Ig domain
for CD4 binding.
Polymorphic residues
of MHC molecules
In Class-I, polymorphic
residues => the
peptide-binding cleft
formed by a1a2 domains
In Class-II, polymorphic
residues => the
peptide-binding cleft
formed by a1b1 domains
In this case HLA-DR,
polymorphism is on b1domain
MHC genes are highly Polymorphic
Expression of MHC alleles is co-dominant
Polymorphism & Polygeny both
contribute to the MHC diversity
Gene conversion creates
new alleles in MHC genes
=> Copying sequences from
one MHC gene to another
Gene recombination creates new
alleles in MHC genes
MHC expression
on cells-I
MHC expression
on cells-II
Expression of MHC
molecules is increased by
cytokines produced during
innate & adaptive immune
cells, e.g. IFN
Features of Peptide-MHC interactions
1. MHC molecules show a broad spectrum for peptide binding,
in contrast to the fine specificity of Ag recognition by Ab.
2. Peptide-MHC interactions are non-covalent and mediated by
residues both in the peptides and in the clefts of MHC
molecules.
3. Each MHC molecule binds one peptide at a time but can bind
many “different peptides”.
4. MHC molecules DO NOT discriminate between
“Foreign Peptides” & “Self Peptides”.
Outline
• Structures & Features of T-cell
antigen receptor (TCR)
• Structures & Features of Major
Histocompatibility Complex (MHC)
• Antigen presentation to T cells
• Summary & Question
Key Concepts in Ag presentation
between APCs & T cells
1. Most T cells recognize only peptides, whereas B cells can
recognize peptides, lipids, nucleic acids,….etc.
NK-T cells can recognize lipids.
2. T cells only recognize peptides displayed by MHC molecules
on Ag-presenting cells (APCs).
3. APCs are responsible for capturing and displaying different
Ags to T cells.
4. APCs serve two key functions for T cell activation:
1st function => process protein Ags to small peptides
=> form & present the peptide-MHC complex to
T cells
2nd function => provide 2nd co-stimulatory signals, e.g.
Cytokines & Surface Molecules
Features of Ag recognition by T cells
T cells require APCs to respond to
a specific Ag
Functions of different APCs
Features of different APCs
Dendritic cells –
The Most
effective APCs
1. Located at common
sites of entry of microbes
2. Express receptors to
capture microbes.
3. Migrate preferentially to Tcell zones in LNs.
4. Mature DCs express high
levels of costimulators
=> T-cell activation.
Overview of Dendritic cells in Ag
capture & presentation
MHC Restriction of
cytotoxic T cells
MHC Restriction-II
For their work leading to the
discoveries regarding the
specificity of cell mediated
immunity
=>MHC-restriction for T cell
recognition => Adaptive
immunity
Class I vs Class II MHC pathway
The Class II MHC pathway of Ag
Presentation
The Class I MHC pathway of Ag
Presentation
Pathogen presentation by MHCs
Ag Presentation to different T cell
subsets
SUMMARY
1. TCR functions to recognize Ag peptides presented by
MHC complexes => Ag peptide specificity
=> MHC restriction
2. Two classes of MHC molecules.
- Class-I MHC => peptides from cytosolic (intracellular)
proteins => CD8 T cells
- Class-II MHC => peptides from extracellular (exogenous)
proteins from phagocytosis => CD4 T cells
3. APCs serve two key functions for T cell activation:
1st function => process & present Ag peptides w/MHC to T
cells
2nd function => provide 2nd co-stimulatory signals, ex.
cytokines & surface molecules
Questions
What is the Bare Lymphocyte
Syndrome?
What is the advantage of MHC
Polymorphism? Is that good if MHC is
as diverse as Ig or TCR?