Lecture 4: Antigen Presentation by T lymphocytes

Transcription

1 Lecture 4: Antigen Presentation by T lymphocytes

2 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?

3 Presentation of Peptide to CD8 or CD4 T Cell by Class I MHC or Class II MHC Molecules, Respectively

4 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

5 Expression of MHC Alleles is Codominant

6 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?

7 Structure of MHC Class I Molecule Heterodimer of membranespanning -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

8 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

9 Polymorphism in the MHC Molecules is Restricted to the Peptide-Binding Cleft

10 Peptides Bind to MHC Class I Molecules Through Anchor Residues Unique for Each MHC Molecule

11 Structural Basis For the Tight Binding of Peptides: Limited in Length Within the MHC Class I Cleft

12 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

13 Structural Representation of Anchor Residue Binding of Peptides Within the MHC Cleft T cell epitopes Peptide MHC Class I molecule Anchor Residues From Dr. Stanley Nathenson

14 MHC Class II molecules can present a diverse yet limited number of peptides sized amino acids long. What is the structural basis permitting MHC Class II molecules to present longer peptides than MHC Class I molecules?

15 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

16 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

17 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 charged aspartic acid (D) or glutamic acid (E) Position 9 is hydrophobic tyrosine (Y), leucine (L), proline (P) or phenylalanine (F).

18 Class I MHC or Class II MHC Molecules Present Peptides to CD8 or CD4 T Cells Respectively

19 MHC Molecules Contain Binding Sites For Either CD4 or CD8

20 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 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

21 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

22 Cells Contain Two Intracellular Compartments: The Vesicular Which Communicates With the Extracellular Fluid and Cytosol Which Does Not

23 The Compartmental Localization of Pathogen Determines the Destination of Its Peptides

24 Peptides Presented by MHC Class I Molecules Are Derived From Intracellular Proteins

25 The Proteosome Generates Peptides of Equivalent Size From Proteins

26 The TAP Molecule Transports Peptides Into the Lumen of the Endoplasmic Reticulum

27 Cytosolic Proteins Are Degraded and Transported Into the ER Where They Can Bind to MHC Class I Molecules

28 Peptides Presented by MHC Class II Molecules Are Derived From Extracellular Proteins

29 The Phagolysosome Generates Peptides of Different Sizes From Proteins

30 MHC Class II Molecules Are Exported From the ER With Its Cleft Containing the Invariant Chain

31 Processing of Invariant Chain to CLIP Peptide

32 Peptides Derived From Exogenous Antigen Replace the CLIP Peptide in the MHC Class II Molecule Cleft in the Endosome

33 Class I MHC or Class II MHC Molecules Present Peptides to CD8 or CD4 T Cells Respectively

34 The T Cell Receptor Specifically Recognizes Sequences in the MHC Molecule and the Peptide it is Presenting

35 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

36 Differences Between Peptide Processing of Class I and Class II MHC Molecules Class I MHC Class II MHC Peptide Source Peptide loading Peptide used for folding T cell interaction Cellular sequela of presentation Endogenous Endoplasmic reticulum Antigen-derived peptide CD8+ T cell Death Exogenous Endosome CLIP peptide CD4+ T cell Activation

37 Tetramers Can Identify and Quantify Ag-specific T Cells

38 MMWR May (1980; 29: ) 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

39 Necrotizing Rash Associated With Toxic Shock Syndrome

40 Superantigens Bind Directly to the TCR and Activate T Cells

41 Immunological Synapse From Grakoui, et al Science,1999 Vol 285,

42 The Immunological Synapse is Characterized by a Ring of Adhesion Molecules Surrounding T cell Receptor-associated Molecules

43 HIV Co-opts The Immunological Synapse to Enhance Cell-to-cell Transmission Env J Clin Invest. 2004; 114(5):605

44 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?