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Lecture 4: Antigen Presentation by T lymphocytes Questions to - - PowerPoint PPT Presentation
Lecture 4: Antigen Presentation by T lymphocytes Questions to - - PowerPoint PPT Presentation
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
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Presentation of Peptide to CD8 or CD4 T Cell by Class I MHC or Class II MHC Molecules, Respectively
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The Three Loci Encoding MHC Class I (A, B and C) or MHC Class II (DP, DQ or DR) Genes Are Highly Polymorphic
Number of alleles/locus
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Expression of MHC Alleles is Codominant
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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?
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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
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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
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Polymorphism in the MHC Molecules is Restricted to the Peptide-Binding Cleft
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Peptides Bind to MHC Class I Molecules Through Anchor Residues Unique for Each MHC Molecule
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Structural Basis For the Tight Binding of Peptides: Limited in Length Within the MHC Class I Cleft
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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
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Structural Representation of Anchor Residue Binding of Peptides Within the MHC Cleft
MHC Class I molecule Peptide Anchor Residues T cell epitopes
From Dr. Stanley Nathenson
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What is the structural basis permitting MHC Class II molecules to present longer peptides than MHC Class I molecules? MHC Class II molecules can present a diverse yet limited number of peptides sized 13 – 17 amino acids long.
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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
- r pocket able to non-
covalently bind peptides
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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
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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 hydrophobic tyrosine (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
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Class I MHC or Class II MHC Molecules Present Peptides to CD8 or CD4 T Cells Respectively
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MHC Molecules Contain Binding Sites For Either CD4 or CD8
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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
- utside of cleft
Binding affinity Peptide tightly bound Peptide is bound looser T cell interaction CD8+ T cell CD4+ T cell
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How do peptides get into those clefts and what are the functional ramifications
- f this process?
Remember that presentation
- f a foreign peptide in a
Class I MHC molecule to a CD8 T cell is a death sentence
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Cells Contain Two Intracellular Compartments: The Vesicular Which Communicates With the Extracellular Fluid and Cytosol Which Does Not
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The Compartmental Localization of Pathogen Determines the Destination of Its Peptides
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Peptides Presented by MHC Class I Molecules Are Derived From Intracellular Proteins
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The Proteosome Generates Peptides of Equivalent Size From Proteins
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The TAP Molecule Transports Peptides Into the Lumen of the Endoplasmic Reticulum
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Cytosolic Proteins Are Degraded and Transported Into the ER Where They Can Bind to MHC Class I Molecules
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Peptides Presented by MHC Class II Molecules Are Derived From Extracellular Proteins
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The Phagolysosome Generates Peptides
- f Different Sizes From Proteins
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MHC Class II Molecules Are Exported From the ER With Its Cleft Containing the Invariant Chain
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Processing of Invariant Chain to CLIP Peptide
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Peptides Derived From Exogenous Antigen Replace the CLIP Peptide in the MHC Class II Molecule Cleft in the Endosome
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Class I MHC or Class II MHC Molecules Present Peptides to CD8 or CD4 T Cells Respectively
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The T Cell Receptor Specifically Recognizes Sequences in the MHC Molecule and the Peptide it is Presenting
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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
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Differences Between Peptide Processing
- f 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
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Tetramers Can Identify and Quantify Ag-specific T Cells
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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
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Necrotizing Rash Associated With Toxic Shock Syndrome
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Superantigens Bind Directly to the TCR and Activate T Cells
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Immunological Synapse
From Grakoui, et al Science ,1999 Vol 285, 221-227
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The Immunological Synapse is Characterized by a Ring of Adhesion Molecules Surrounding T cell Receptor-associated Molecules
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HIV Co-opts The Immunological Synapse to Enhance Cell-to-cell Transmission
Env
J Clin Invest. 2004; 114(5):605
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