Adaptive Immunity: Antigen Capture & Presentation to Lymphocytes Flashcards
MHC I
Macrophages - APC
B Lymphocytes - APC
MHC I
- MHC class I is composed of an a chain with three domains: a1, a2, a3. The a chain non-covalently pairs with a protein called b2-microglobulin (b2m). This partnering with b2m stabilizes the MHC class I molecule.
- Class I peptides are usually 8-11 amino acids long and are presented to CD8 T cells. They usually fit precisely into the class I binding site.
- HLA Class I: Three different genes (and molecules) ; HLA-A, -B and -C
- MHC-I is expressed on ALL nucleated cells.
MHC II
- • MHC class II is composed of 2 transmembrane glycoproteins (2 chains and 4 domains): a1-a2 and b1-b2.
- Class II peptides are between 11 and 22 amino acids long and are presented to CD4 T cells. They often protrude on both sides of the class II binding site.
- HLA Class II: Three different pairs (a and b) of genes; HLA-DP, -DQ and –DR; more than 3 class II molecules due to cross-pairing (e.g. DPa with DQb).
- MHC-II is mainly expressed on “professional” antigen presenting cells (APC): dendritic cells (DC), macrophages and B cells.
MHC class I molecules survey the [] environment and therefore are key in defending against [].
MHC class I molecules survey the intracellular environment and therefore are key in defending against viruses, intracellular bacteria and parasites, and tumors.
MHC class II molecules dominantly survey the [] compartment and orchestrate the response against [].
MHC class II molecules dominantly survey the extracellular compartment and orchestrate the response against extracellular microbes.
Why is “naked” MHC not generally found on the cell surface?
Empty (“naked”) MHC is not generally found on the cell surface, because the molecule falls apart without a stably bound peptide (quality control); so if a MHC is not occupied by a foreign peptide, it will be occupied by self peptides (this is most often the case), to which our T cells should not react due to T cell tolerance
- The polypeptide chains of the MHC molecules are translated on the rough endoplasmic reticulum (ER). Here the molecule is correctly folded and the chains assembled to create the MHC molecule.
- MHC-I molecules are receptive to the peptides when they are made in the ER – their peptide-binding site is unoccupied. They can sample and bind peptides in the ER, including those made by degradation of cytosolic material.
- For loading of MHC-I molecules, cytosolic peptides are actively transported from the cytosol into the ER by a complex of transporters associated with antigen processing (TAP-1 and TAP-2) proteins.
- Proteins made (translated) in the cytoplasm are broken up into peptides by the Proteasome (a multi-enzyme complex), which recycles all cellular proteins.
TAP-1 and TAP-2 transporters translocate these peptides into the ER where some peptides fit into the groove of newly synthesized MHC class I. Other peptides will be trimmed to fit, whereas many will not fit at all (although some may fit other MHC molecules).
- Peptides that fit will stabilize the MHC-I molecule and allow it to be transported to the cell surface where effector CD8 T cells will scan the peptide content on an MHC molecule. If there is no infection, all MHC class I molecules will be occupied by peptides from normal self proteins, and T cells will not react to them.
- If a cell is infected with an intracellular microbe (e.g. a virus) then viral proteins will also be processed and will occupy some MHC class I molecules. CD8 T cells specific for that viral epitope will recognize viral peptides presented by MHC-I molecules and can destroy the infected cell carrying such molecules.
- The polypeptide chains of the MHC molecules are translated on the rough endoplasmic reticulum (ER). Here the molecule is correctly folded and the chains assembled to create the MHC molecule.
- MHC-II molecules have their peptide-binding site BLOCKED by the invariant chain. They are not supposed to pick up peptides from the ER, but will do so later on their way to the cell surface.
- APCs phagocytose extracellular microorganisms (an extracellular bacterium or other foreign invader), or antigens/particles.
- Phagocytosed material sits in a vesicle (phagosome), which fuses with lysosomes that contain proteolytic enzymes. Degradation of the invader’s proteins into peptides begins in this phagolysosome.
- The phagolysosome then fuses with an MHC-II-containing vesicle that buds from the endoplasmic reticulum (ER).
- The MHC-II peptide-binding site is blocked by the invariant chain (Ii) so that it cannot accept peptides in the ER.
- In the phagolysosome, the invariant chain dissociates from the MHC-II peptide-binding site under low pH and allows peptides to access the binding site.
- Peptides which fit MHC-II bind in the groove and stabilize the MHC class II molecules.
- The vesicle moves from the cytoplasm to the cell surface where MHC class II presents foreign peptide to CD4 T cells. If there is no infection, all class II molecules will be occupied with self-peptides and T cells will not react.
- If there is infection, then CD4 T cells specific for this particular invader will be stimulated.
- MHC-II is only expressed on the surface of professional antigen-presenting cells: dendritic cells, B cells, and macrophages. This pathway is NOT operational in other cell types.
As naïve T cells can only be activated by mature dendritic cells (see above), what would happen if a particular virus didn’t infect mature DC, but only infected endothelial cells? How could you activate CD8 T cells to control this infection?
- Cross-presentation
- Cross-presentation is a specialized pathway that operates only within dendritic cells.
- Cross-presentation breaks the “rule” that internalized antigens are presented by MHC-II molecules to CD4 T cells - cross-presenting DC are able to shuttle the antigens internalized from the extracellular environment into cytosolic (proteasomal) Ag processing pathway and onto MHC-I molecules (which we know typically only present intracellular antigens).
- During cross-presentation, some DC ingest other dying infected cells, process the ingested material into antigens, and cross- present these antigens on MHC-I molecules to activate naïve CD8 cells
