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MICR 304 Immunology &
Serology
Lecture 9
TCR, MHC molecules
Chapter 3.10 – 3.19, 4.9- 4.11, 5.1 – 5.19
Overview of Today’s Lecture
• Generation of T cell receptor (TCR)
• MHC molecules
• Antigen presentation via MHC molecules
Key Players in Immunology
Innate
Adaptive
Cells
Phagocytes
Epithelial Cells
NK Cells
Lymphocytes
(B-Ly, T-Ly)
Effector molecules
Complement
Antimicrobial
(Poly)Peptides
Antimicrobial
Lipids?
Antibodies
T Cell Receptor
• 2 chains
– Connected by disulfide
bond
– Variable region
– Constant region
– Short cytoplasmic tail
• Mostly a and b chain
• Some specialized Tcells have g and d
chain (gd T cells)
T-Cell Receptor Belongs to the
Immunoglobulin Super Family
Gene Segments Coding for the
T-Cell Receptor
• Variable region of a-chain is composed of V
and J gene segments
• Variable region of b-chain is composed of V,
D and J gene segments
Generation of the TCR by Gene
Rearrangement and Recombination
No secondary modification of TCRs
Diversity of the Lymphocyte
Antigen Receptors
P- and N- nucleotides: nucleotides added during initial gene rearrangement and recombination
Unique Properties of TCR
Compared to BCR
• Only one antigen binding site
• Never secreted
• Recognize processed antigen presented
through specialized molecules
TCR Recognizes Antigen
Presented by MHC Molecules
• MHC: major histocompatibility
complex
• First identified in
transplantation immunology
• T cells recognize antigen bound
to an MHC molecule
• Two types of MHC molecules
– MHC I: presents endogenous
peptides
MHC I
CTL
– MHC II: presents exogenous
peptides
MHC II
TH
• Virus encoded
• Produced by intracellularly
replicating microorganisms
• Tumor antigens
• Uptake through phagocytosis and
degradation in phagolysosome
Antigen Recognition through TCR
Requires Additional Molecules
• CD4: Interaction with MHC II
• CD8: Interaction with MHC I
TH
• CD3: signal transduction
CTL
Cytokines
Ag presenting cell Any nucleated cell
Cytotoxic
granules
Contrast TH Cells and CTL
TH
CTL
CD on surface
CD4
CD8
MHC
Interaction
Target cells
MHC II
MHC I
APC (macrophages,
DC, B cells, others)
Cytokine release
Any nucleated cell
Response
upon
activation
Cytotoxic granule
release (and some
cytokines)
gd T cells are Distinct
• Minority of T cell population
• Bind heat shock proteins and
nonpeptide ligands
– Mycobacterial lipid antigen
– Phosphorylated ligands
• Not restricted by classical MHC I or
MHC II molecules
• May bind to free antigen
Expression of MHC Molecules
Differs Between Tissues
• MHC I positive: any
nucleated Cell
• MHC II positive: only
antigen presenting cells
(APC)
– IFNg can MHC II in other
cells
• APC: take up antigen,
degrade it, load it onto
MHC II and present it at
their cell surface
– Human activated T cells
– Microglia in brain
Structure of MHC Molecules
MHC I
• Endogenous peptides
are bound to MHC I by
their ends
– Ionic interaction
• 8 – 10 aa
MHC II
• Exogenous peptides are
bound to MHC II along
the groove
• 13 - 17 aa
Intracellular Compartment
Exogenous
peptides
Endogenous compartment
Subcellular Location of Pathogens
and their Products
Endogenous Ag
Engage CTL
Exogenous Ag
Engage TH cells
Key Molecules in Antigen
Presentation
MHC I
MHC II
• Proteasomes
• TAP1, 2 (Transporters
associated with antigen
processing)
• CD8
• Lysosomal proteases
• CLIP (class II associated
invariant chain peptide)
• B7
• CD4
• CD28
On target cell
On CTL
On APC
On TH
Loading of Endogenous Peptides
onto MHC I (1)
• Chaperones guide in ER nascent MHC I to
TAP
• Endogenous proteins are degraded in
proteasome and enter ER through TAP
• Peptide loading occurs in the ER
• If peptides are too long they can be trimmed
the endoplasmic reticulum aminopeptidase
associated with antigen processing (ERAAP)
• MHC I with peptide loaded is sent to cell
surface
Loading of Endogenous Peptides
onto MHC I (2)
Viral Strategies to Interrupt
Active
LearningofExercise:
Presentation
Viral Peptides
• Blocking entry of viral peptides into ER
By
which mechanisms
could
• Retention
of MHC I in ER
• Degradation
of MHCwith
I via transport
of
viruses
interfere
the
MHC I into cytosol
presentation of viral peptides on
• Blocking access of CTLs to surface
MHC
I at the
cellloaded
surface?
expressed
peptide
MHC I
Loading of Exogenous Peptides
onto MHC II
Loading of Exogenous Peptides onto
MHC II (1)
• MHC II leaves ER with CLIP
– CLIP
• Class II associated invariant-chain peptide
• Binds to peptide groove
• Prevents premature peptide loading
• MHC II vesicle fuses with phagosome
containng degraded exogenous peptides
• HLA-DM removes CLIP from MHC II peptide
groove and exogenous degraded peptide can
bind
– HLA-DM is MHC II like
Loading of Exogenous Peptides onto
MHC II (2)
Limitations in MHC Binding
Pose a Problem
• How can so many different pathogen
derived peptides be presented?
•Introduce variability in MHC molecule
•MHC is polymorphic
•MHC is polygenic
Polymorphism and Polygeny
Increase Variability
• Polymorphism
– Numerous variants (alleles) for each gene
– MHC genes are the most polymorph genes known
• Polygeny
– Several different genes for MHC I and MHC II
– A set of genes with a broader range of peptide binding is
expressed
Genes Coding for MHC Molecules
Polygeny
• 3 genes and gene
products for MHC I
– A (a)
– B (a)
– C (a)
– b2 microglobulin is
monomorphic
• 3 genes and 4 gene
products for MHC II
– DR (a, b1, b2)
– DP (a,b)
– DQ (a,b)
Polymorphism
• Over 1000 alleles
• Alleles are codominant expressed
Number of Different Alleles
Polymorphism of MHC Genes
… a growing list!
Allelic Variation Occurs at Specific
Sites with in the MHC Molecules
The Expression of MHC Alleles
is Co-Dominant
Intra- and Interpersonal
Variability of MHC Molecules
• Within a person multiple MHC molecules are
expressed
– 3 MHC I genes x 2 (father, mother) = 6 MHC I
– 4 sets of MHC II genes x 2 (father, mother) = 8
MHC II
• Cells within a person are uniform
• Cells from another persons carry different
sets of MHC molecules!
T Cell Recognition of Antigens is
MHC Restricted
MHC molecules participate in antigen recognition.
Superantigens
• Antigens that are not
processed
• Crosslink TCR with MHC
• Can simultaneously
stimulate 2 - 20% of all T
cells.
Non-Classical MHC Genes
•
•
•
•
•
Resemble MHC class I genes in structure
Many associate with b2microglobulin
Also called MHC Ib
Comparatively little polymorphism
Some bind to activating NK cell receptors (NKG2D)
– Example: MIC-A
– Induced in response to cellular stress
– Trigger cytotoxicity
• Some bind to NK inhibitory receptors (NKG2A)
– Example: HLA E
– Inhibit cytotoxicity
– Found on fetus derived placental cells
• Some present lipid antigen to T cells
– Example CD1
Refresher: NK Cell Mediated Killing
Today’s Take Home Message
• The TCR consists of two chains, a and b, and is similar
to the arm of an antibody molecule with the TCR a-chain
representing the light chain and the b-chain the heavy
chain.
• T cell recognize digested peptide presented through MHC
molecules.
• T helper cells recognize peptide on MHC II and utilize
CD4 to ensure proper binding to MHC II.
• CTL recognize peptide on MHC I and utilize CD8 to
ensure proper binding to MHC I.
• MHC are polymorphic and polygenic.
• Non-classical MHC I molecules (MHC Ib) interact with
inhibitory and activating NK cell receptors.