Both CD4+ and CD8+ T cells can recognize antigen ONLY when it has been processed and presented on the cell membrane of an APC or Target Cell (respectively) in association with self MHC. This phenonmenon has been termed: Restriction to Self MHC.
In this terminology, CD4+ T cells are Class II MHC restricted while CD8+ T cells are Class I MHC restricted.
By convention, the cells which present antigen to CD4 Th cells are termed antigen presenting cells while the cells which present antigen to CD8 Tc cells are termed target cells.
Processing= protein antigen is degraded into peptides
Presentation= association of peptide with MHC and transportation of MHC/peptide complex to the cell membrane
These peptides are derived from proteins that are synthesized within the cytoplasm of the cell, thus this pathway is also termed the cytosolic pathway.
Examples: viral proteins, proteins synthesized by intracellular protozoa or bacteria.
Protein levels are carefully regulated in the cell. Misfolded, aged or damaged proteins are naturally degraded within the cytoplasm of all nucleated cells.
Proteins targeted for proteolysis often have a small protein known as UBIQUITIN associated with them. Such conjugates are known to be degraded within structures known as PROTEOSOMES (basically a cylinder composed of hydrolytic enzymes which functions as a large protease complex)
Degradation is thought to occur within the hollow center of the cylinder.
Two alternative subunits of the proteasome (termed LMP2 and LMP7) are encoded within the MHC complex and their synthesis is triggered by the Th cell cytokine, IFN-gamma.
The proteolytic activities of these two subunits apparently generates peptides which preferentially bind to Class II MHC proteins.
Peptides generated in the cytoplasm are transported across the membrane of the RER by a transporter protein known as the TAP protein. The TAP protein is a heterodimer composed of two subunits known as TAP1 and TAP2. The term TAP refers to "transporters associated with antigen processing"
Interestingly, the genes for TAP 1 and TAP 2 map to the Class II region of the MHC complex.
Meanwhile..... Class I MHC alpha chains are being synthesized by the cell at ribosomes associated with the RER. An alpha chain must associate with a beta-2- microglobluin molecule and a processed PEPTIDE before it is transported to the golgi----> plasma membrane. A molecular chaperone known as calnexin binds to the alpha chain and to beta-2-microglobulin. This complex then binds to the TAP protein, the peptide is "captured" from the TAP protein causing calnexin to dissociate from the complex.
The "completed" Class I MHC protein + peptide can now be transported to the Golgi in membrane-bound vesicles for further modification, packaging and sorting to the plasma membrane.
The presentation of Class I MHC/ peptide by a target cell to a CD8+ Tc cell results in TARGET CELL KILLING.
Performed only by specialized antigen presenting cells:
macrophages
B lymphocytes
Dendritic Cells
Dendritic cells are the most effective antigen presenting cells in that they constitutively produce a high level of Class II MHC protein and the co-stimulatory protein, B-7.
B cells constitutively express the Class II MHC protein but must be activated to produce B-7.
Macrophages must be induced (activated) by the process of phagocytosis before expressing class II MHC or B7.
In addition, there is a category of cells known as: NON-Professional APCs that can act as APCs for short periods of time, particularly during periods of sustained inflammatory activity. Such cells must be induced to express both Class II MHC and B7.
Macrophages internalize antigen primarily by phagocytosis
B lymphocytes internalize antigen by receptor-mediated endocytosis
[membrane-bound Ig serves as the receptor and antigen serves as the ligand] We have discussed properties of the B cell epitope {on the surface of antigen, hydrophilic, segmental mobility, etc.]
Within the endocytic pathway (B lymphocytes) or the phagocytic pathway (Macrophages) - protein antigens are processed by proteolytic enzymes into peptides [13-18 amino acids in length]. For example, B lymphocytes internalize antigen through receptor mediated endocytosis. In this process, surface Ig bound to antigen is internalized in clathrin-coated vesicles. As this vesicle becomes an early endosome, the pH drops to 6-6.5 and the clathrin can be recycled to the plasma membrane. The vesicle then becomes a late endosome with a pH of 5-6 and finally a lysosome with a pH of 4.5-5. The lysosome contains a battery of over 50 different hydrolytic enzymes including: proteases, nucleases, lipases, glycosidases, etc.
At this stage, proteins associated with the antigen are degraded (hydrolyzed) by proteases into peptides.
Meanwhile...... Class II MHC molecules are translated at ribosomes associated with RER. The 2 polypeptide chains [designated alpha & beta] enter the RER where they attach to each other and bind to a third protein known as Ii - the invariant chain. The presence of the invariant chain prevents the binding of endogenously synthesized peptides from binding to the Class II MHC molecule. Membrane-bound vesicles traffic the MHC Class II to the endosomal (or phagosomal in the case of macrophages) pathway. Under acidic conditions within these vesicles, Ii is replaced with peptide. The Class II MHC/ peptide complex is then transported to the plasma membrane where it is inserted.
The Class II MHC/peptide complex is now presented to a CD4+ Th cell. The result of this interaction is: CLONAL EXPANSION---->DIFFERENTIATION TO EFFECTOR or MEMORY Th CELL.
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