Download Lecture 4: Antigen Presentation by T lymphocytes

Lecture 4: Antigen Presentation by T lymphocytes
Questions to Consider
 What is the structural basis by which MHC
molecules present peptides to the T cell
receptor?
 How are endogenous peptides targeted to
MHC Class I molecules and exogenous
peptides targeted to MHC Class II molecules?
 How does the T cell receptor see the peptide
and MHC molecule?
 What is the structural basis for CD4 T
cells/MHC Class II and CD8 T cell/MHC Class I
restriction?
Presentation of Peptide to CD8 or CD4 T Cell by
Class I MHC or Class II MHC Molecules, Respectively
Number of alleles/locus
The Three Loci Encoding MHC Class I (A, B and C) or
MHC Class II (DP, DQ or DR) Genes Are Highly Polymorphic
Expression of MHC Alleles is Codominant
Class I MHC molecules can
present a diverse yet limited
number of peptides sized
8 – 10 amino acids long.
What is the structural basis
that limits the peptides that
the MHC molecule can
present?
Structure of MHC Class I Molecule
 Heterodimer of membrane-
spanning -chain and
2-microglobulin
 The -chain is polymorphic
while the 2-microglobulin is
the same for everyone
 The 1 and 2 domains form
a cleft or pocket able to noncovalently bind peptides
Peptides Are Bound Within MHC Class I Molecules by
Hydrogen Bonds and Ionic Interactions Between Amino
Acids in the Peptide Ends and the MHC Molecule
Polymorphism in the MHC Molecules is
Restricted to the Peptide-Binding Cleft
Peptides Bind to MHC Class I Molecules Through
Anchor Residues Unique for Each MHC Molecule
Structural Basis For the Tight Binding of Peptides:
Limited in Length Within the MHC Class I Cleft
Some Residues of the Peptide in the MHC Molecule
Are Aligned Toward MHC Binding Clefts
and Others Toward the T Cell Receptor
From Dr. Stanley Nathenson
Structural Representation of Anchor Residue
Binding of Peptides Within the MHC Cleft
T cell
epitopes
Peptide
MHC Class I
molecule
From Dr. Stanley Nathenson
Anchor
Residues
MHC Class II molecules
can present a diverse yet
limited number of peptides
sized 13 – 17 amino acids long.
What is the structural basis
permitting MHC Class II molecules
to present longer peptides than
MHC Class I molecules?
Structure of MHC Class II Molecule
 Heterodimer of
membrane-spanning
-chain and -chain
 The -chain and chain are polymorphic
 The 1 and 1
domains form a cleft
or pocket able to noncovalently bind
peptides
Part of the Peptide Is Bound to MHC Class II Molecules
by Hydrogen Bonds and Ionic Interactions Between
Amino Acids in the Peptide and the MHC Molecule
Peptides of Variable Length Bind to MHC Class II
Molecules Through Structurally Related Anchor Residues
At Various Distances From the Ends of the Peptide
Position 1 has
hydrophobic
residues
Position 4 is negatively Position 9 is hydrophobic
tyrosine (Y), leucine (L),
charged aspartic acid
(D) or glutamic acid (E) proline (P) or phenylalanine (F).
Class I MHC or Class II MHC Molecules Present
Peptides to CD8 or CD4 T Cells Respectively
MHC Molecules Contain Binding
Sites For Either CD4 or CD8
Structural Differences between Class I MHC and
Class II MHC Molecules and Their Consequences
Class I MHC
Class II MHC
Structure
-chain and
2-microglobulin
-chain and -chain
Peptide size
8-9 amino acids
13-17 amino acids
Cleft
Peptide must be
within cleft
Ends of peptide can dangle
outside of cleft
Binding affinity
Peptide tightly bound
Peptide is bound looser
T cell
interaction
CD8+ T cell
CD4+ T cell
How do peptides get into
those clefts and what are
the functional ramifications
of this process?
Remember that presentation
of a foreign peptide in a
Class I MHC molecule to a
CD8 T cell is a death sentence
Cells Contain Two Intracellular Compartments:
The Vesicular Which Communicates With the
Extracellular Fluid and Cytosol Which Does Not
The Compartmental Localization of Pathogen
Determines the Destination of Its Peptides
Peptides Presented by MHC Class I Molecules
Are Derived From Intracellular Proteins
The Proteosome Generates Peptides of
Equivalent Size From Proteins
The TAP Molecule Transports Peptides Into
the Lumen of the Endoplasmic Reticulum
Cytosolic Proteins Are Degraded and
Transported Into the ER Where They Can
Bind to MHC Class I Molecules
Peptides Presented by MHC Class II Molecules
Are Derived From Extracellular Proteins
The Phagolysosome Generates Peptides
of Different Sizes From Proteins
MHC Class II Molecules Are Exported From the
ER With Its Cleft Containing the Invariant Chain
Processing of
Invariant Chain to CLIP Peptide
Peptides Derived From Exogenous Antigen
Replace the CLIP Peptide in the
MHC Class II Molecule Cleft in the Endosome
Class I MHC or Class II MHC Molecules Present
Peptides to CD8 or CD4 T Cells Respectively
The T Cell Receptor Specifically Recognizes
Sequences in the MHC Molecule and
the Peptide it is Presenting
Alloreactivity May Be Due to Heightened Affinity of
a T Cell Receptor to a Different Nonself Peptide
Alone or a Nonself Foreign MHC Molecule Alone
Differences Between Peptide Processing
of Class I and Class II MHC Molecules
Class I MHC
Class II MHC
Peptide
Source
Endogenous
Exogenous
Peptide
loading
Endoplasmic reticulum
Endosome
Peptide
used for
folding
Antigen-derived peptide
CLIP peptide
T cell
interaction
CD8+ T cell
CD4+ T cell
Cellular
sequela of
presentation
Death
Activation
Tetramers Can Identify
and Quantify Ag-specific T Cells
MMWR May 23 1980
(1980; 29: 229-30)
 National surveillance data, first MMWR report
 55 cases of TSS from 8 states; 31 from
Wisconsin
 52 (95%) cases in women
 38 (95%) of 40 (known history) onset during
menses
 33 (73%) of 45 had S. aureus isolated from
mucosal site
 Case fatality rates: 13% overall: 3.2% (1/31)
in Wisconsin, 25% (6/24) in 7 other states
Necrotizing Rash Associated
With Toxic Shock Syndrome
Superantigens Bind Directly
to the TCR and Activate T Cells
Immunological Synapse
From Grakoui, et al Science ,1999 Vol 285, 221-227
The Immunological Synapse is Characterized
by a Ring of Adhesion Molecules Surrounding
T cell Receptor-associated Molecules
HIV Co-opts The Immunological Synapse
to Enhance Cell-to-cell Transmission
Env
J Clin Invest. 2004; 114(5):605
Questions to Consider
 What is the structural basis by which MHC
molecules present peptides to the T cell receptor?
 How are endogenous peptides targeted to MHC
Class I molecules and exogenous peptides
targeted to MHC Class II molecules?
 How does the T cell receptor see the peptide and
MHC molecule?
 What is the structural basis for CD4 T cells/MHC
Class II and CD8 T cell/MHC Class I restriction?