ANTIGEN PROCESSING AND PRESENTATION

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.