Antigen Processing and Presentation Notes (MHC I & II)

Review: Antigen Recognition and MHC Basics

• B cells and T cells recognize different types of antigens.
• B cells can recognize a variety of macromolecules including proteins, polysaccharides, nucleic acids, and lipids.
• T cells can recognize only protein antigens in the form of peptides; these peptide fragments must be presented to T cells as an MHC-peptide complex.
• There are two MHC molecule classes: Class I and Class II.
• MHC Class I molecules present peptides derived from intracellular pathogens (pathogens that live and replicate inside human cells, e.g., viruses).
• Under normal conditions, peptides derived from the cytosol of any nucleated cell are displayed by MHC Class I as an MHC-peptide complex.
• When a cell is infected by an intracellular pathogen (e.g., virus), MHC Class I molecules present virus-derived peptides for recognition by T cells.
• MHC Class II molecules present peptides derived from extracellular pathogens (extracellular pathogens live and replicate outside human cells; e.g., extracellular bacteria, toxins, parasites).
• Antigen Presenting Cells (APCs) internalize extracellular pathogens and break them down into peptide fragments; these fragments are presented by MHC Class II molecules for recognition by T cells.
• Antigen processing is the process by which pathogens and their products are degraded to produce peptide antigens; these peptide fragments combine with MHC molecules inside the cell.
• The MHC peptide complex thus formed travels to the cell surface where it displays the peptide fragment to T cells.
• In this video, we explore: (1) how peptide fragments from pathogens and their products are produced, (2) how these fragments are combined with MHC molecules, and (3) how MHC-peptide complexes are presented to T cells.
• We will first study the processing and presentation of intracellular or endogenous antigens.
• This pathway involves the nucleus, rough endoplasmic reticulum (ER), and Golgi apparatus as key cellular components.
• The target cell is the virus-infected cell where antigen processing will occur.

Endogenous Antigen Processing and MHC Class I Presentation (Endogenous Pathway)

• When a virus infects a cell, it uses the cell’s machinery to synthesize viral proteins in the cytoplasm of the target cell.
• These viral proteins are taken up and digested in a large barrel-shaped structure called the proteasome.
• Proteasomes are present in the cytoplasm of all cells and are composed of $12-15$ protein subunits.
• The proteasome has proteolytic activity and degrades cytosolic proteins into peptide fragments; these fragments are typically about $8-15$ amino acids long.
• The peptide fragments are transported to the rough endoplasmic reticulum (ER) through a pore formed by a transporter known as the transporter associated with antigen processing, abbreviated as TAP.
• TAP consists of two subunits, $ext{TAP}<em>1$ and $ext{TAP}</em>2$.
• The alpha chain and beta chain of the MHC Class I molecule are synthesized and translocated into the ER.
• These chains are assembled together, and a group of chaperone proteins brings the MHC Class I molecule near the TAP site.
• Once the peptides have entered the ER, they bind to the MHC Class I peptide-binding groove.
• The MHC Class I–peptide complex is then released from the chaperones and moves to the cell surface via the Golgi apparatus.
• Upon reaching the cell surface, the complex integrates into the membrane and can be recognized by T cells.
• For recognition, T cells possess T cell receptors (TCRs) that recognize the peptide presented by MHC molecules, and they also carry a coreceptor, CD8, which recognizes the
  $ext{C} ext{D}8$ (CD8) interaction with the $ext{α}_3$ domain of MHC Class I.
• Thus, T cells interact with both the peptide and the MHC molecule on the surface of the target cell.
• Because this pathway involves MHC Class I molecules, it is also known as the MHC Class I antigen presentation pathway.