12. antigen processing & presentation to T lymphocytes

where does antigen presentation occur during the initiation of T cell responses?

secondary lymphoid tissues (spleen, lymph nodes) to naive T cells

where does antigen presentation to effector T cells occur?

can occur in all tissues

antigen presentation by migratory dendritic cells

• antigens are captured by dendritic cells → become activated

• dendritic cells migrate to paracortex (lymph nodes)

• present antigen to naive T cell

vesicular cellular compartment

• membrane-bound organelles (separated by membranes)

• communicates with extracellular environment → endo/exocytosis

• ex. golgi, endosomes, lysosomes

cytosolic cellular compartment

communicates intracellularly → between nucleus & cytoplasm

what two important factors regulate the pathway of antigen processing & presentation?

1. source of proteins

   • extracellular

   • intracellular

2. intracellular location of the protein

   • endosomes

   • cytoplasm

extracellular/vesicular antigens are processed by what pathway?

exogenous/endocytic pathway - MHC II (presented to CD4+ cells)

• endocytosis of extracellular foreign protein antigen

what type of vaccines utilize the exogenous/endocytic pathway?

inactivated or purified protein vaccines

cytosolic antigens are processed by what pathway?

endogenous/cytosolic pathway - MHC I (presented to CD8+ cells)

• endogenous synthesis of foreign protein antigen (ex. viruses, listeria, mRNA)

what types of vaccines utilize the endogenous/cytosolic pathway?

• live viral/vectored vaccines

• mRNA vaccines

what is cross presentation?

extracellular protein processed through the endogenous/cytosolic pathway → MHC I → present to CD8+ cells

what cells can cross-present?

dendritic cells only

which cells can present antigen to CD8+ T cells?

all nucleated cells (express MHC I)

ubiquitin

when conjugated to other proteins, flags protein for degradation

proteasome

filled with proteases → cytosolic proteolysis 

MHC I (endogenous/cytosolic) pathway general steps

1. production of proteins (ex. viral proteins) in cytosol

2. proteolytic degradation of ubiquinitinated proteins (via proteasome in cytosol)

3. peptides transported from cytosol to rough ER (TAP1 & 2)

4. complexes with MHC I in the ER

5. peptide-MHC complex packaged into exocytic vesicles and expressed on surface

what do chaperone proteins do?

stimulate α and β chains of MHC molecules to complex together in ER

transporters associated with antigen processing (TAP) - TAP1 & TAP2

translocate peptides from cytoplasm into ER for loading onto MHC class I molecules (located in ER membrane)

what is the physiological significance of MHC I-associated antigen presentation?

cell killing by CD8+ cytotoxic T lymphocytes

what cells can present antigens to CD4+ T cells?

professional antigen presenting cells

• dendritic cells

• macrophages

• B cells

why can professional antigen presenting cells present to CD4+ cells?

1. express MHC II molecules

2. ability to perform endocytosis

3. ability to process endocytosed antigens

   • (can internalize & process extracellular proteins)

MHC II (exogenous/endocytic) pathway general steps

1. uptake of extracellular proteins into vesicular compartments

2. proteins broken down by proteases in endosome

3. MHCII transported from ER to endosome

4. proteolytic degradation of invariant chain & CLIP removal

5. peptide-MHC interaction in endosome

6. expression on cell surface

invariant chain

• binds to MHC II & blocks peptide binding groove → prevents peptide loading onto class II molecules in ER

• involved in trafficking of MHC molecules to peptide-containing acidified endosomes

class II-associated invariant chain peptide (CLIP)

piece of invariant chain that remains in peptide binding groove after proteolytic degradation

HLA-DM

catalyzes removal of CLIP from peptide binding groove to allow peptide loading onto MHC II molecule (in endosome)

what is the physiological significance of MHC II-associated antigen presentation?

• immune response against extracellular pathogens

• production of antibodies

  • B cells present peptide-MHC complex to T cells → T cells help B cells produce Abs

what is the physiologic significance of cross presentation?

DCs can present microbial/tumor antigens from infected/neoplastic cells to CD8+ cells → prime CD8+ T cells to target infected/neoplastic cells