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 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 Number of alleles/locus

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 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 T cell epitopes Peptide MHC Class I Anchor molecule Residues From Dr. Stanley Nathenson

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 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 hydrophobic Position 1 has Position 4 is negatively tyrosine (Y), leucine (L), hydrophobic charged aspartic acid proline (P) or phenylalanine (F). residues (D) or glutamic acid (E)

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  -chain and  -chain and  -chain Structure  2-microglobulin Peptide size 8-9 amino acids 13-17 amino acids Peptide must be Ends of peptide can dangle Cleft outside of cleft within cleft Binding affinity Peptide tightly bound Peptide is bound looser T cell CD8+ T cell CD4+ T cell interaction

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

Invariant Chain to CLIP Peptide Processing of

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 Endogenous Exogenous Source Peptide Endoplasmic reticulum Endosome loading Peptide used for Antigen-derived peptide CLIP peptide folding T cell CD8+ T cell CD4+ T cell interaction Cellular sequela of Death Activation presentation

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?