Chapter 3: Antigen Capture & Presentation to LΦ

MHC Restriction

• T-LΦ only see peptides displayed by MHC molecules (T receptor recognizes AAs from antigen and AAs from MHC molecules

• Effector T cells must see antigen a second time to continue to proliferate

Class-I MHC

• Displays only cytosolic/intracellular proteins processed from proteasome in the ER

• CD8

Class-II MHC

• Displays only internalized extracellular proteins processed from endolysosome

• CD4

Chaperone

Anti-Hapten Ig

Two Classifications of Dendritic Cells

Langerhans cells (Classical)

• Most common and locate in skin, tissues

• Major cytokines release are TNF, IL-6, IL-12, IL-23

• Express chemokine receptor CCR7 that direct cells to T-cell zones of LN

• Major activation of naive-T cells

Plasmacytoid DC

• Locate in blood and tissues

• Release type-I IFN

• Antiviral defense state, minor activation of of naive-T cells (also contains CCR7)

MHC Genetic Locus

• Principal determinant of tissue graft acceptance or rejection

• Only twins and inbred animals have identical MHC loci hence accept grafts

• Graft rejection is not a biological phenomenon (natural occurrence). MHC molecules design to be highly polymorphic so everyone can recognize different peptides so no single microbe can eliminate the entire mankind

• Present on chromosome 6 in humans as MHC haplotype

MHC Haplotype

• Set of 2 alleles (1 from each parent) that contain Class II and class I MHC locus

• 6 different class I & II molecules (3 from each parent)

• Codominantly expressed

MHC I Loci

1. HLA-A

2. HLA-B

3. HLA-C

MHC-II Loci

1. HLA-DP (DPα + DPβ)

2. HLA-DQ (DQα + DQβ)

3. HLA-DR (DRα + DRβ1 ± DRβ 3/4/5)

Class-I MHC Structure

3 α chain (α1, α2, α3)

• Peptide-binding cleft made up of α1, α2 (polymorphic)

• Invariant α3 that binds to only CD7 coreceptor (Cytotoxic T-cells). Activate only when simultaneously recognize by peptide in the cleft & α3 of MHC-I

1 β2m (microglobulin)

• Noncovalent bond to alpha chain

• Encode by gene outside MHC (chromosome 15)

Class-II MHC Structure

2-alpha chains

2-beta chains

• Peptide binding cleft is made up of α1 and β1 (polymorphic)

• Nonpolymorphic α2 and β2 bind to only CD4 coreceptor (Helper T cells)

MHC Molecules

• Another term is Human Leukocyte Antigens (HLA)

• Can only bind peptide and only one at a time

• Even in severe infection state, only 1% of MHC displays microbial antigen. The rest are self-antigen

Ubiquitin-Proteasome Pathway

• Intracellular proteins tagged with ubiquitin to be broken down by enzyme-complex proteasome

• Transporter for antigen processing (TAP): transport peptides from cytosol to ER

• Tapasin is a chaperone ER proteins that load peptides onto MHC-I molecules

• MHC-I-peptide complex is stable and transports to cell surface