Flashcards in Lecture 8, Ag Presentation Deck (44):
Name the immune cells that present class II MHC.
Which is/are not phagocytic?
DCs, macrophages, monocytes, B cells
- B cells are not phagocytic
What are macrophages known as in the liver?
What are macrophages known as in the brain?
What are DCs known as in the skin?
Langerhans' cells (form a continuous cellular sheet at the junction of the dermis and epidermis)
What are DCs known as in the T lymphocyte area of lymph nodes?
What are DCs known as in the B lymphocyte area of lymph nodes?
Where else are these cells found? (1 place)
- Spleen as well
Name the 2 main classes of DCs.
1. Plasmacytoid DC (we won't focus on these much)
2. Conventional DC
What do plasmacytoid DCs do?
Produce copious amounts of interferons (antiviral agents)
What do conventional DCs do? (what we talk about in this class)
Phagocytosis, Ag-presentation, and trafficking to the regional lymph node.
W/o naming proteins, generally describe class I MHC processing s/p viral infection. (also occurs for tumor cell)
- Viral protein infects cell
- Viral protein synthesized in the cytoplasm
- Peptide fragments of viral proteins bound to MHC class I in ER
- Bound peptides/MHC I xported to cell surface
- Presents to CD8+ T cells
W/o naming proteins, generally describe class II MHC processing.
- Ag taken up into neutral endosome
- Endosomal acidification activates proteases, digest invading protein
- Fusion of this w/another vesicle containing MHC class II
- Presentation on cell surface to CD4+ T cells
What 2 major proteins make up the proteasome?
LMP2 and LMP7
Is the proteasome associated w/class I or II MHC processing?
Where is the proteasome located?
Class I (digests foreign peptides)
Although most of the time there is no foreign protein to digest by the proteasome, the cell still must present its MHC class I. What 2 things can be presented instead?
- Old proteins (70%)
- DRiPs (defective ribosomal particles, 30%)
Where does MHC class I synthesis take place?
Prior to beta-2 microglobulin binding the MHC class I in the ER, what protein is bound to the partially folded MHC class I?
- Calnexin (a chaperone)
Once beta-microglobulin binds the partially formed MHC class I protein to make a fully functional MHC class I in the ER, what chaperone changes occur?
- Calnexin leaves
- Calreticulin and ERp57 (chaperone complex) binds
Still in the ER, the fully formed alpha-beta MHC class I is now bound to the calreticulin and ERp57 chaperone complex. This can then associate w/the protein ____________ via ___________.
TAP, via tapasin
(TAP: transporter associated w/Ag processing)
Once the alpha-beta MHC class I is binding calreticulin, ERp57, and TAP (via tapasin), what does TAP do?
Delivers peptides that were digested by the proteasome (either from viral protein, normal protein, or DRiPs)
(TAP then releases the MHC class I to go to cell surface)
What's the name of the protein in the ER that cleaves proteins into smaller fragments after they've already been degraded by the proteasome but prior to their insertion into the MHC class I binding groove?
Prior to MHC class II-containing endosomes binding w/phagolysosomes (containing digested foreign peptide), what important protein is associated w/the MHC class II molecules and why?
Invariant chain (Ii)
- Keeps self peptides/misfolded proteins out of the binding cleft
In an endosome w/MHC class II and bound invariant chain, what is the next step that occurs?
What protein remains in the MHC's groove?
- Invariant chain is fragmented, but a piece of it called CLIP (class II associated invariant peptide) remains in the groove
Now we have an acidified endosome w/class-II MHC and CLIP bound to the binding groove. Once this endosome binds the phagolysosome, how can digested foreign Ag become incorporated into the MHC class II binding groove?
HLA-DM binds the class II HLA
(allows CLIP to cleave and foreign peptide to enter; MHC then travels to cell surface)
(Not important) What protein serves as a negative regulator for HLA-DM?
DO (DOA and DOB)
Generally speaking, what is the response of a CD4+ T cell once it binds specifically to an APC and is activated?
T cell proliferation and differentiation
What are the 2 subsets of CD4+ T helper cells?
What is the general role of each?
- Th1: macrophage activation
- Th2: B cell activation (-> AB synthesis)
(To a lesser extent Th1 cells can also activate B
cells to produce ABs)
What APC or T cell interaction do B cells need to bind/recognize Ag?
Nothing, they can bind Ag directly (they are APCs)
Generally, what do Th1 cells produce that activates macrophages?
How does this change the macrophage?
- Th1 cytokines make macrophages very active and helps them engulf and destroy some invaders that they otherwise wouldn't, such as mycobacterium tuberculosis
Generally, what do Th1 cells produce that activates B cells?
How does this change the B cell?
- Required for growth, class switching, differentiation into plasma cells, etc.
Upon encountering Ag, an APC becomes highly active. Besides presenting Ag via MHC, what other receptor does the APC initially express?
Co-stimulation is required for an APC to activate a T cell. What receptor found on T cells must bind B7 of APCs?
If an activated APC binds the MHC of a T cell, but said APC doesn't initially express B7 (to bind CD28 of T cell), how can B7 expression be stimulated in the APC?
- T cell is stimulated to make and express CD40 ligand (CD40L), which binds CD40 of APC.
- This leads to APC's expression of B7
What receptors are required for a Th2 (helper) cell to bind a B cell, differentiate it into a plasma cell, and secrete ABs?
- First MHC II binds TCR + B7 binds CD28
- Next T cell is stimulated to produce CD40L, binds CD40
- Cytokine receptors are produced on B cell, and cytokines are released by T cell
The mechanisms of sustained TCR engagement to an APC is the formation of a specialized contact, termed the ________________________.
What's the name of the outer ring of the immunological synapse?
What general type of proteins are found here?
- pSMAC (peripheral)
- Adhesion molecules
What's the name of the inner ring of the immunological synapse?
What general type of proteins are found here?
- cSMAC (central)
- Signaling molecules
Name the actual proteins found in the cSMAC (center of immunological synapse).
TCR, CD4, CD28, MHC:peptide, CD8, PKC-theta
Name the actual proteins found in the pSMAC (periphery of immunological synapse).
Name the 3 general steps that occur when an APC binds a T cell.
- How are the different proteins arranged in each step.
1. Junction formation
- Adhesion proteins toward the center
2. MHC-peptide transport
- cSMAC proteins start to move to the center
- cSMAC in center, pSMAC in periphery
What can CD8+ CTLs do after they bind their target cell?
Release cytolytic granules that can destroy their target
MHC class I molecules under normal conditions (in the absence of foreign ag) are loaded with self peptides derived from the normal degradation of self cellular
proteins. MHC class II molecules, under normal conditions, are thought to contain only _________ in their peptide binding groove.
What are the major differences b/w immature and mature DCs, in terms of phagocytosis, Ag presentation, and T cell activation?
Do both produce B7?
- Resting (immature) APCs (e.g. DCs) are highly phagocytic but do not present Ag particularly well
- S/p phagocytosis of an Ag, DCs mature and present Ag very well to T lymphocytes
- Unlike immature DCs, mature DCs express on their surfaces large amounts of co-stimulatory molecules, e.g. B7 (also known as CD80 and CD86), and can also produce large quantities of cytokines required for T lymphocyte proliferation and differentiation.
Generally, what happens to the T cell when it correctly binds its immunological synapse w/a DC?
T cell proliferates and differentiates