Antigen Processing and Presentation Ag processing: degradation of proteins into peptides Ag presentation: binding of peptide by MHC molecule and displaying the complex on the cell surface Cytosolic (endogenous) pathway Endocytic (exogenous) pathway Class IClass II 11 22 33 2m2m 11 22 11 22

Two compartments of the cell Extracellular pathogens Endocytic vesicles (exogenous) Class II CD4 T cells Degraded in Peptides bind to Presented to Intracellular pathogens Cytosol (endogenous) Class I CD8 T cells Cytosol: continuous with nucleus Vesicular system (ER, golgi, endosomes, lysosomes): continuous with extracellular fluid

nucleusER Cytosolic pathway 1. Site of peptide generation 2. Site of membrane protein synthesis 3.Transport of peptides into ER 4.Loading of peptide onto nascent class I molecules in ER 5.Display the complex on the cell surface Golgivesicle Plasma membrane

Cytosolic pathway nucleusERGolgivesicle Plasma membrane

Pathogen exploitation nucleusERGolgivesicle Plasma membrane Human Cytomegalovirus (HCMV): US2 and US11 bind and remove nascent class I  chain from ER US18 mimics HLA-E X US3 prevents class I from egress from ER US6 blocks TAP

Endocytic pathway 1.Site of peptide generation 2.Site of MHC class II synthesis 3.Loading of peptide into class II molecules 4.Surface expression Plasma membrane Y Y Y Y

Endocytic pathway Y Y Y Plasma membrane Y

Influenza A Virus Segmented RNA virus 8 RNAs 10 proteins 15 HA 8 NA H5N1

vRNA (-)Virion cRNA (+) mRNA (+) protein Virion RNA Complementary RNA Messenger RNA RNA pol RNA polymerase No proof-reading No repair High mutation rate 1.5 x /nt/cycle Antigenic Drift: a series of mutations that occur over time and cause a gradual evolution of the virus Seasonal Influenza Epidemics

HA and NA are highly variable

Antigenic Shift: an abrupt change in the HA and/or the NA proteins resulting in a new subtype of the virus Influenza Pandemics Cell Co-infection Reassortment

Interferons inhibit protein synthesis and therefore virus replication

CD8CD4BClearance (days)% Survival Role of T and B cells in responses to influenza virus infection > > > >200

Host-Influenza Virus Interaction HostInfluenza virus 5’ triphosphate5’ cap TLR7, RIG-IdsRNA, NS1 APOBEC NK cells AntibodyHA and NA (antigenic shift) CTLEpitope change (antigenic drift)

Principles of adaptive immunity TCR recognition Antigen presentation and processing Host defense against viruses