T Cell Receptor (TCR) & MHC
Complexes-Antigen Presentation
• Pin Ling (凌 斌), Ph.D.
ext 5632; lingpin@mail.ncku.edu.tw
• 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
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)-I
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 peptides 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.
Key Concepts in TCR-II
5. Like Ab (or BCR), TCR diversity is generated by VDJ
recombination.
6. gd T cells function differently from ab T cells in MHCindependent manner.
Similarities & Differences between
T-cell Receptor (TCR) and Ab
The Structure of T-cell Receptor (TCR)
Murine T-cell Receptor (TCR) genes
1. Two types of TCR, ab and gd, serve distinct functions
2. VDJ recombination for TCR
T-cell Receptor (TCR) vs. Ab
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)
Binding of a TCR to a peptide-MHC
complex
Front
Side
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
Allele-specific peptides from MHC
molecules
MHC genes are highly Polymorphic
Expression of MHC alleles is co-dominant
Polymorphism & Polygeny both
contribute to the MHC diversity
Polymorphism vs Polygeny of MHC
1. MHC molecules are polygenic. Every individual contains
several different MHC-I & MHC-II genes with wide
ranges of peptide-binding specificity.
=> Personal protection
2. MHC is highly polymorphic. Multiple variants of each
MHC gene within the population function as a whole.
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
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
CD1 is an MHC-I-like molecule
presenting lipid antigens
Lipid antigens presented by CD1
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 advantage of MHC
Polymorphism? Is that good if MHC is
as diverse as Ig or TCR?