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?