Antigen Recognition by T Lymphocytes

1.            Generation of T-cell ligands

a.         T-cell recognition of Antigen:

i.          the actions of T cells depend on their ability to recognize cells that are harboring pathogens or that have internalized pathogens or their products.

ii.          T cells do this by recognizing peptide fragments of pathogen-derived proteins in the form of complexes of peptide and MHC (major histocompatibility complex) molecules on the surface of these cells.

b.         Major intracellular compartments:

i.          the cytosol is contiguous with the nucleus via the nuclear pores in the nuclear membrane.

ii.          the vesicular system comprises the endoplasmic reticulum, Golgi apparatus, endosomes, lysosomes, and other intracellular vesicles.

iii.         all cell-surface proteins, including MHC class I and MHC class II molecules, are synthesized on ribosomes attached to the cytoplasmic face of the endoplasmic reticulum and co-translationally transported into the lumen, where are they modified and folded.

c.            Infectious agents can replicate in either of the two distinct intracellular compartments.

d.            Pathogens in cytosol:

i.          viruses and certain bacteria replicate in the cytosol or in the contiguous nuclear compartment.

ii.          they are eliminated by cytotoxic T cells which are distinguished by the cell-surface molecule CD8.

iii.         this is an important means of eliminating sources of new viral particles and cytosolic bacteria and thus freeing the host of infection.

e.            Pathogens in vesicular compartments:

i.          these are detected by the CD4 T cells.

ii.          the TH1 cells activate macrophages to kill the intravesicular bacteria and harbor, and the TH2 cells activate B cells to make antibody.

iii.         some bacteria, such as mycobacteria, invade macrophages and flourish in intracellular vesicles.

iv.         other bacteria, which normally proliferate outside cells, secrete toxins and other proteins, and these and bacterial degradation products can be internalized by cells by endocytosis.

f.          Antigen processing and presentation:

i.          to produce an appropriate response to infectious microorganisms, T cells need to be able to distinguish between foreign materials coming from the cytosolic and vesicular compartments.

ii.          this is achieved through delivery of peptides to the cell surface from each of these intracellular compartments by a different class of MHC molecule.

iii.         MHC class 1 molecules deliver peptides originating in the cytosol to the cell surface, where the peptide:MHC complex is recognized by CD8 T cells.

iv.         MHC class II moelcules deliver peptides originating in the vesicular system to the cell surface, where they are recognized by CD4 T cells.

v.         since the generation of peptides from an intact antigen involves modification of the native protein, it is called antigen processing while the display of the peptide at the cell surface by the MHC molecule is referred to as antigen presentation.

g.            Presentation of MHC proteins to T cells:

2.         MHC proteins

a.         MHC class I proteins are glycoproteins found on the surface of virtually all nucleated cells.

b.         MHC class II proteins are glycoproteins found on the surface of certain cells, including macrophages, B cells, dendritic cells of the spleen, and Langerhans cells of the skin.

c.         Antigen presentation by class I MHC:

i.            cytosolic proteins are degraded to peptide fragments by the proteasome, a large multicatalytic protease.

ii.            peptides produced are inaccessible to the MHC class I molecule, which remains bound to TAP-1 (transporters associated with antigen processing-1)

iii.            peptides are transported into the lumen of the ER by the TAP transporter and are ‘inspected’ by the TAP-bound MHC class I.

iv.         when a peptide binds MHC class I tightly, the MHC molecule folds around the peptide and is released from TAP-1.

d.         Antigen presentation by class II MHC:

i.          antigen is taken up into intracellular vesicles.

ii.            acidification of vesicles activates proteases to degraded antigen into peptide fragments.

iii.         vesicles containing peptide fragments fuse with vesicles containing MHC class II.

iv.         bound peptide is transported by MHC class II to the cell surface.

3.            Biologic Importance of MHC

a.         The ability of T cells to recognize antigen is dependent on association of the antigen with either class I or class II proteins

b.         In contrast, B cells do not have that requirement and can recognize soluble antigens in plasma with their surface IgM monomer acting as the antigen receptor.

c.         This requirement to recognize antigen in association with a ‘self’ MHC protein is called MHC restriction.

d.         Many autoimmune diseases occur in people who carry certain MHC genes.

e.         The success of organ transplants is, in a large part, determined by the compatibility of the MHC genes of the donor and recipient.