Intracellular Pathogens Extracellular Pathogens Voet & Voet, Biochemistry

Part 1: Antigen Specific Acquired immunity depends on many specific protein-protein interactions Part 1: Antigen Specific Antibody - Antigen Cytotoxic T-cell receptor - MHC class I protein/peptide complex Helper T-cell receptor - MHC class II protein/peptide complex

Voet & Voet, Biochemistry

Acquired immunity depends on non-specific protein-peptide interactions MHC class II - peptides generated in the endosome/lysosome (antigens of extracellular origin) recognized by helper T cells MHC class I - peptides generated in the cytoplasm (antigens of intracellular origin) recognized by cytotoxic T cells

Antigen Processing and Presentation to Helper T-cell Antigen Internalization e.g., via IgG receptor Endosome/Lysosome

Jardetzky et al., PNAS 93: 734-738 (1996) Peptides bind to MHC Class II molecules in a common polyproline II conformation Jardetzky et al., PNAS 93: 734-738 (1996)

Antigen Recognition by Antibodies (Ab) and T-cell Receptors (TCR) Ab - Ag TCR – MHC/peptide Surface area ~ 2x750 Å2 > 50% hydrophobic 1-2 H-bonds Epitope discontinuous in antigen (Ag) sequence Surface area ~ 2x1000 Å2 Ag peptide contributes only 40% of surface area Epitope continuous in Ag sequence Otherwise similar to Ab - Ag recognition

Peptide Binding by Major Histocompatibility Complex (MHC) Antigen-presenting Proteins MHC I MHC II Peptides of intracellular origin Peptides 9-10 residues long Deep pockets bind peptide sidechains Deep pockets bind peptide N- and C-termini Peptides of extracellular origin Peptides 15 residues or longer Shallow pockets bind peptide sidechains Peptide termini free H-bonds to peptide backbone

Part 2: Transport/Immunoregulatory Acquired immunity depends on many specific protein-peptide interactions Part 2: Transport/Immunoregulatory (a few examples) IgG receptor - IgG MHC class II protein - CD4 MHC class I protein - CD8 IL-2 - CD25 TNF - TNF receptor

Grakoui et al., Science 285: 221-227 (1999) The efficiency of antigen processing may control the T-cell cytokine profile for a given epitope by the size of its “immunological synapse” Grakoui et al., Science 285: 221-227 (1999)