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Kaplan6 - Processing and Presenting Antigen, T cell Activation

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Go through the endogenous pathway of antigen presentation; what uses it, what size antigens, what are the antigens from, and all the components involved?
-Viral proteins (endogenous) are chopped up by proteosomes to about 8-10AA's in length (LMP-2&7 encode proteosome)
-They are transported through TAP (transporter for antigen processing) into the ER to MHC I molecules (associated w tap1&2 proteins)
-The loaded up MHC I molecules are then exocytosed out of the RER, through the golgi, and to the membrane
-Remember, all cells can use this type signaling
Go through the exogenous pathway of antigen presentation; what uses it, what size antigens, what are the antigens from, and all the components involved?
-Antigen from outside the cell (bacteria, etc.) is phagocytosed into endosomes and degraded by lysosomal enzymes (in phagolysosomes) to 10 to 20 AAs in length
-Meanwhile, an MHC II molecules is produced in the rough ER with its α and β chains, and in addition, an INVARIANT CHAIN is also produced, which blocks the binding groove (later by CLIP)
-The blocked MHC II molecule then buds off the RER, goes through the golgi, and eventually fuses with the phagolysosome
-The invariant chain is selectively degraded, thus allowing the exogenous antigen to fuse with the MHC II (requires action of HLA-DM)
-The loaded MHC II is then exocytosed to the membrane
What are the adherence molecules on the T cell vs macrophage during T cell activation?
-T cell; TCR, CD2 (an IgCAM), & LFA-1 (an integrin)
-Mac; MHC II, LFA-3 (an integrin), & ICAM-1 (an IgCAM)

-In addition CD4/CD8 functions in binding to MHC II/I and in signal transduction (along with CD3)
What are the costimulatory molecules for T cell activation on T cell vs macrophage? What encourages this interaction? What is the result of the different interactions?
-T cell; CD4/8, CD28
-Macrophage; MHC II/I, B7

-The B7 molecule is upregulated by TLR (toll-like receptor) interactions with pathogens
-The B7 molecule stimulates the macrophage to release IL-1*, IL-6, & TNF-α (proinflammatory molecules)
-These in turn cause upregulation of IL-2 secretion and receptor expression which finally leads to T-cell proliferation

-The CD4/8, along with CD3 + TCR, leads to T cell activation and secretion of IFN-γ (*activates macrophage*)
Run through the cytokines produced by the T cells vs macrophages, what chain of events stimulates their production, and what do they do?
Macrophage; IL-1*, IL-6, TNF-α
-These are stimulated by pathogen--->TLR--->B7 (binds CD28--->secretion
-Their function (other than inflammation) is to stimulate IL-2 and IL-2 receptor production, leading to T cell proliferation

T cell; IFN-γ, IL-2
-The IFN-γ has release stimulated by T cell activation (from TCR and CD4/8 binding to the MHC). This is the activator of macrophages that turns them into "killing machines"
-The IL-2 is stimulated mostly by IL-1 and leads to T cell proliferation
Where do we find CD2, what class of molecule is it, and what does it bind to?
-On the T cell
-It is an IgCAM
-CD2 binds to LFA-3 (an integrin)
Where do we find CD28, and what does it bind to?
-It is on the T cell (probably others too)
-It binds to B7 (leads to macrophage cytokines)
What is IL-2?
-It is an autocrine cytokine causing proliferation of T cells
What is IFN-γ?
-Produced by activated TH1 cells to activate macrophages
-Also produced by NK cells
What is a superantigen? What does this cause? Molecules responsible? What bacteria produce these?
-They cross link TCR with MHC II molecules without using the antigen specific binding sites (bind to β-TCR chain)
-This will lead to polyclonal activation of TH cells, over-production of IFN-γ, over-activation of macrophages, over-expression of proinflammitory molecules (IL-1, IL-6, & TNF-α), and ultimately, toxic shock
-Common bacteria producing these are staph & strep (staph makes toxic shock syndrome toxin-1)
What are the overall functions of TH1 and TH2 cells?
-TH1 cells handle cell mediated response (i.e. they activate macrophages and CTLs)
-TH2 cells do humoral (i.e. activate B cells)
What molecules are responsible for TH0 cell differentiation to TH1 and TH2 cells?
-TH1 cells are created when there is IL-12 or IFN-γ around
-IL-12 is from macrophages
-IFN-γ is from NK or already active TH2 cells
-In other words, TH1 cells are activated when the innate system has been activated

-TH2 cells are made from high levels of IL-4
-IL-4 is initially made by TH0 cells in higher and higher amounts as they do not receive signals from innate cells
-After activation, TH2 cells produce IL-4 in high amounts
After differentiation, what do TH1 and TH2 cells produce. Which are inhibitory to the alternate pathway. What do those cytokines do?
TH1 cells produce;
-IFN-γ: activate macrophages and more TH1 cells, inhibits TH2 cells
-IL-2: T cell proliferation (esp. CTL)
-TNF-β: proinflammatory (cell mediated cell stimulation)

TH2 cells produce;
-IL-4,5,6,10, & 13: 4-6 activate B cells, 4 & 10 inhibit TH1 differentiation, 4 calls for more TH2 cells
-TGF-β: Call for TH0---->THreg&17

-notice that both produce cytokines to up-regulate themselves and down regulate the other pathway
What are THreg cells? What identifies them? What is their overall function? What calls for them?
-They are one of two minor classes of TH cells
-They have CD25 as a marker and produce FoxP3
-They secrete anti-inflammatory cytokines such as IL-10 and are critical in PREVENTING AUTOIMMUNITY
-Remember, IL-10 inhibits TH1 cells
-TGF-β (transforming growth factor) dictates their production (comes from TH2 cells)
What are TH17 cells? What identifies them and what do they produce? What have they been associated with? What calls for them?
-They are one of two minor classes of TH cells
-They are identified by transcription factor RORgammat and by their production of proinflammatory cytokine IL-17
-They have been associated with tissue damage in autoimmune diseases
-TGF-β + IL-6 dictates their production (come from TH2 cells)
What makes IL-12 and what does it do?
-Produced by macrophages
-Takes TH0----> TH1
What is the difference between tuberculoid and lepromatous leprosy? How are each stimulated? What clinical finding other than appearance differentiates the two?
-Tuberculoid is much less severe that lepromatous, although it still leads to some skin damage from rashes
-Tuberculoid results from the cell mediated approach where granuloma formation is used to eradicate the bac.

-Lepromatous ensues when humoral immunity is stimulated. Ineffective antibodies are produced and the bac. is left to reproduce unchecked in macrophages leading to disfiguring infections
-With lepromatous, you often get hypergammaglobulinemia (from lots of Igs)

-Remember that humoral and cell mediated both inhibit the other and encourage themselves, so once the body goes down the humoral path, you're screwed
What specifically do IL-4 and IL-5 do in terms of B cell activation?
-Both promote class switching
-IL-4-----> IgG & IgE
-IL-5-----> IgA
What kind of TH cell would people with allergies be more likely to have increased levels of?
-Of TH2, because they are the ones that increase humoral response
-Specifically, they make IL-4 which calls for IgE from B cells (as well as IgG)
CD8 interacts with what on presenting cells? What does CD4 interact with?
-CD8 interacts with α-3 subunit of MHC-1 receptors
-CD4 interacts with β-2 subunit of MHC-2 receptors
Where does the antigen bind to on MHC I vs. MHC II and about what size?
-MHC I; α1 and α2 make the groove for an 8-10AA peptide
-MHCII; α1 and β1 make the groove for a 10-20AA peptide
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