• 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.