• Not all peptides will bind to all MHC
• They bind to MHC through Anchor Residues and the amino and carboy terminus
• 
  
• No specificity other that what is able to bind in MHC cleft

• The T Cell Receptor recognizes BOTH the peptide and MHC molecule
• Very specific interaction-even a single residue change can be distinguished
• Contact Residue
• Anchor Residue
• Polymorphic Residue
• Pocket of MHC

• Pathogens are constantly evolving and changing their peptide makekup
• Evasion of MHC presentation also occurs (EX. Malaria parasites infect red blood cells - no MHC
• The vast diversity of MHC is belived to protect the population as whole from being completely wiped out by single pathogen - Natural immunity to pathogens (HIV, Malaria, Ebola)

• The set of HLA genes from one parent
• HLA typing is done using panels of monoclonal antibodies specific for the different allelic products or by PCR using specific primers

• Due to MHC diversity, a complete match between donor and recipient is unlikely
• MHC 'mis-match' is the primary reason for tissue regection - Graft vs. Host disease
• T cells see MHC as foreign, non-self material
• HLA typing (extensive) used to screen for closest donor match

• Cytosolic (intracellular Antigens)
• degraded in cytosol 
• MHC I
• Effector CD8 T cells
• Cell death
• Endocytic (extracellular Antigens)
• Endocytic vesicles (low pH)
• MHC II
• Efector CD4 T cells
• Activation of B cells to secrete Ig to eliminate extracellular bacteria/toxins

Peptide loading of MHC I

• Newly synthesized MHC I heavy chain molecules associate with TAP and B2M (beta2microglobulin)
• Certain peptides bind and stabilize the complex of heavy chain and B2M
• Peptides/class I HLA heavy chain/B2M ternary complexes move through ER, Golgi, and then cell surface

• Partly folded MHC I alpha chains bind to calnexin until B2M binds
• MHC class I complex is released from calnexin, binds a complex of chaperone proteins (calreticulin, ERp57) and binds to TAP via tapasin
• Cytosolic proteins and defective ribosomal products (DRiPs) are degraded to peptide fragments by the proteosome. TAP delivers peptides to ER
• A peptide binds the MHC I molecule and completes folding. The MHC I is released from the TAP complex and exported to cell membrane

• Assist in folding of MHC I
• Association w/ B2M
• Binding Peptide

• Degrades misfolded, defective, and aged proteins in cytoplasm
• Exists in two forms: CONSTITUTIVE proteosome (all cells) and IMMUNOPROTEOSOME (in all cells stimulated with interferons)
• Immunoproteosome conatians: all induced by interferons to alter enzymatic specificity of proteosome
• LMP2
• LMP7
• MECL-1 
• Further cleavage of peptides occurs in the ER by aminopeptidase (ERAAP), tailoring them to binding MHC I molecules

• Associate with antigen processing (TAP1/2)
• Bring Peptides to ER
• Bind MHC I

• Produced by viruses interfere with antigen processing

Processing of extracellular Antigens by acidic pH-activated proteases occurs in endosomes

1. Ag taken up from extracellular space to intracellular vesicles
2. Endosomal proteases inactivate in neutral pH
3. Acidification (vesicles) activates proteases to degraded antigen (peptides)
4. Vesicles w/ peptides fuse w/ vesicles containing MHC II

1. Ii: blocks binding of peptides & misfolded proteins (MHC II)
2. Ii cleave in acidified endosome (CLIP) - still bound
3. CLIP blocks binding of peptides to MHC II
4. HLA-DM releases CLIP and allows binding MHC II - cell surface

1. Ii binds in MHC II groove
2. Ii is cleaved - initially to leave a fragement bound to MHC II and to membrane
3. Further cleavage leaves short peptide fragment, CLIP, bound to the MHC II molecule

• MHC I:
• Phagolysosome
• Antigens
• ER
• Phagosome
• MHC II:
• CD4 binding 
• Auto-phagosome
• Self antigens

• Conventional (T Cell activatiors)
• CCR7, CCL18
• ICAM-2
• LFA-1
• CD58, CD11c
• B7.1, B7.2
• Plasmacytoid (Anti-Viral mediators that may help conventional DCs to sustain IL-12 production
• CXCR3
• IFN-Beta
• TLR-7, TLR-9
• INF-alpha
• BDCA-2

1. TCR ligation by peptide-MHC molecule (signal 1)
2. Ligation of CD28 on the T cell by B7 (co-stim) on the APC (signal 2)
3. Cytokines bound to corresponding receptors on the T cell surface (signal 3)

• If T cells receive signal 1 w/out signal 2 such was was found to occur w/ paraformaldehyde-fixed macrophages pulsed with peptide Ag, the T cells is rendered anergic or non-responsive to Ag

• The co-stimulatory molecule B7 on the DC binds CD28 on the naive T cell
• W/out signal 2 cell is rendered anergic-non responsive to antigens