Generalizations
- T-cells recognize foreign protein antigens if these are displayed within the cleft of MHC displayed on the PM.
- The protein antigen must be degraded into peptides by a sequence of events called antigen processing.
- The degraded peptides then associate with MHC molecules with the cell interior and this peptide-MHC complex is transported to the membrane, called antigen presentation.
- Peptides which associate with Class I and class II MHC molecules are processed in different intracellular compartments.
- Class I MHC molecules bind peptides which are derived from endogenous antigens and are processed in cytoplasm (e.g. normal cellular proteins, tumor proteins, and viral or bacterial ).
- Class II MHC molecules bind peptides which are derived from exogenous antigens and are processed by endocytic pathway. These antigens are internalized by phagocytosis or endocytosis)
Self-MHC Restriction of T-cells
- Both CD4+ and CD8+ can recognize antigen only when it is presented by a self-MHC molecule, an attribute called self-MHC restriction.
- CD4+ TH cells recognize antigen with class II MHC molecules on APCs.
- CD8+ Tc cells recognize antigen with class I MHC molecules on target cells.
Role of antigen presenting cells
- A primary antibody response and cell-mediated response were induced by a protein in its native conformation
- A secondary response (mediated by a B-cells) could be induced only by native antigen.
- A secondary cell-mediated response could be induced by either the native or the denatured antigen.
- Most cells can present antigen with class I MHC.
- Presentation with class II MHC is restricted to APCs.
- Processing of antigen is required for recognition by T-cells.
Professional APCs
- Dendritic cells are most effective APCs. These constitutively express high levels of class II MHC and co-stimulatory activity. They can activate naïve TH cells.
- Macrophages must be activated by phagocytosis of particulate antigens before express class II MHC or co-stimulatory B7 .
- B-cells constitutively express class II MHC molecules but must be activated before they express co-stimulatory molecules.
Antigen Processing
- Endogenous antigens are degraded into peptides within the cytosol by proteasomes and assemble with class I molecules in RER.
- Exogenous antigens are interanalized and degraded within the acidic endocytic compartments and pair with class II molecules.
- Peptide binding to class II molecules involves replacing a fragment of invariant chain in the binding cleft by a process catalyzed by non-classic MHC molecule HLA-DM.
- Presentation of nonpeptide (lipid and glycolipid) antigens derived from bacteria involves class I-like CD1 molecules.
Endogenous Pathway
(Cytosolic pathway)
- The pathway by which endogenous antigens are degraded for presentation with class I MHC utilizes the same pathways involved in the normal turnover of intracellular proteins.
- Intracellular proteins are degraded into short peptides by a cytosolic proteolytic system present in all cells.
- Ubiquitin-protein conjugates can be degraded by a multifunctional protease complex called a proteasome.
- Peptides generated in the cytosol by the proteasome are translocated by TAP( transporter associated with antigen processing) into the RER that requires hydrolysis of ATP.
- TAP favors peptides with hydrophobic or basic carboxyl-terminal amino acids, the preffered anchor residues for class IMHC molecules.
- Peptides assemble with class I MHC aided by chaperone molecules.(calnexin, calreticulin, Tapasin)
Exogenous Pathway
(Endocytic pathway)
- The binding of antigenic peptide to class I or II MHC is dictated by the mode of entry into the cell or by the site of processing.
- APCs can internalize antigens by phagocytosis, endocytosis or both.
- Macrophages internalize antigen by both processes.
- Most of the APCs are not phagocytic and therefore internalize antigen receptor mediated endocytosis.
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