Post on 06-Mar-2020
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
The Three Loci Encoding MHC Class I (A, B and C) or MHC Class II (DP, DQ or DR) Genes Are Highly Polymorphic
Num
ber o
f alle
les/
locu
s
Expression of MHC Alleles is Codominant
Class I MHC molecules can present a diverse yet limited
number of peptides sized8 – 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 non- covalently 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
MHC Class I molecule
Peptide
AnchorResidues
T cellepitopes
From Dr. Stanley Nathenson
What is the structural basis permitting MHC Class II molecules
to present longer peptides than MHC Class I molecules?
MHC Class II moleculescan present a diverse yet
limited number of peptidessized 13 – 17 amino acids long.
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 non- covalently 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 9 is hydrophobictyrosine (Y), leucine (L),proline (P) or phenylalanine (F).
Position 4 is negatively charged aspartic acid (D) or glutamic acid (E)
Position 1 has hydrophobic residues
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
CleftPeptide must be
within cleftEnds 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 aCD8 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 Intothe 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
presentationDeath 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?