After infection and proliferation what percent of T cells will recognize the pathogen?
10-20%. This is part of the clonal selectio theory
What cell brings the antigen to the LN to interact with T cells? Where do T cells enter the LN? Where to DC enter the LN?
-T cells enter LN through the HEV (High Endothelial Venule)
-DC enter with antigen through the afferent lymphatic vessel
What are the components of the TCR complex?
TCR alpha and beta with CD3(and greek letters) at the bottom.
TCR alpha and beta connect with the Ag from MHC and CD are responsible for transmitting the signal. The CD are homodimers
Describe the afffinity of the TCR-MHC interaction?
It is low affinity.
10^-4 to 10^-5 for TCR affinity
Also low affinity are antibodies, adhesion molecules, and growthfactors.
-point is you need something else helping out (co-receptors)
What is one of the most important co-receptors and its ligand for activating T-cells? what type of T cells?
CD28 (on the T-cell) binds with B7-1 or B7-2 (on the APC)
-CD28 is on CD4 cells because the interactions is with MHC II and professional APCs
-the co receptor enhances interactions between the T cells and the APC
-and the Co-receptors provides signals required for T-cell activation and differentiation
What are the important Co-receptors and their ligand on B cells, DCs, and Macrophages (professional APCs)?
CD4 binds with MHC II
CD28 binds with B7-1/2
What is the important co-receptor found on Endothelial cells, fibroblasts, macrophages, and DCs probably important for extravasation?
on the T-cells is LFA-1 which is a dimer of CD11a and CD18 this binds with the Ligand ICAM-1 on the APC
What are the important receptors on activated T-cells?
CD25 (IL-2Ralpha) binds with IL-2 expressed on T cells
CD154 (CD40L) binds with CD40 expressed on B cells, DCs, and macrophages
What are the important inhibitory receptors on activated T cells?
CTLA-4 bins with B7-1/2 expressed on B cells, DCs, and Macrophages (this competes with CD28)
PD-1 binds with PD-L1 expressed on B cells, DCs, and Macrophages
What are the 3 steps of TCR signaling pathways?
1. Receptor Ligation
2. Phosphoylation of ITAMS (Immunoreceptor Tyrosine-Based Activation Motifs) by Lck (protein tyrosine kinase)
3. Recruitment and activation of ZAP-70 (protein tyrosine kinase)
After recruitment of ZAP-70 what are the down stream pathways options?
1. PLC gamma -> Diacylglycerol (DAG) -> NF-kB
2. PLC gamma -> Inositol triphosphate (IP3) -> NF-AT
3. Mitogen activated protein kinases (MAPK) -> AP-1
Describe the detailed activation of NF-kB
1. Ligand binding
2. Phosphoylation of ITAM by Lck
3. Recruitment and activation of ZAP-70
4. ZAP-70 activates PLC gamma --> Diacylglycerol (DAG) --> Protein Kinase C (PKC) --> which phosphorylates inhibitor of kB kinase (IkK). IkK phosphorylation and ubiquination targets it to the 26s proteasome, this allows the free NF-kB to translocate to the nucleus and transcribe genes.
-NF-kB induces IL-2, IFN-gamma, TNF- alpha
Describe the detailed activation of NF-AT
PLC gamma is activated by ZAP-70.
PLCgamma --> IP3 -->IP3receptor on the ER releasing Ca2+ from the ER into the cytoplasm.
Ca2+ causes Calmodulin to bind with Calcinuerin and activate it.
Activated Calcineurin will dephosphorylate NF-AT thus allowing it to translocate to the nucleus
NF-AT in the nucleus will induce IL-2, IL-4, IFN-gamma, ad TNF-alpha
What is the drug that targets the NF-AT pathway and how does it work?
Cyclosporine and Tacrolimus target the NF-AT pathway by inhibiting the dephosphorylation of NF-AT by inhibting calcineurin
What does the AP-1 induce?
Describe the mTOR pathway in detail?
PI3-K --> Akt --> mTOR --> protein translation
What is the mTOR inhiitor?
In the timeline of binding, when does CTLA-4 get expressed?
CTLA-4 is a negative regulatior that also binds B7-1/2 competing with CD28.
-CTLA-4 is expressed after TCR ligaton
What is the drug that inhibits CD28, how is it made, and how does it work?
Abatacept (co-receptor blockage)
-made by the fusion of the extracellular domain of CTLA-4 with the Fc region of IgG1
-it binds to B7-1/2 and prevents CD28 from being activated. Results in T cell anergy
-indicated in rheumatoid arthritis
What are the three signals T cells require for activation?
1. TCR ligation
2. Co-receptor ligations (enhances TCR signaling such as CD28)
3. Cytokine stimulation (paracrine- from the APC, and autocrine: IL-2)
What do the IL-Receptor family all share in common?
They all have a cytoplasmic gamma chain, most are dimer but IL-2 and IL-15 are timers with alpha, beta, and gamma units
Describe the signaling pathway gamma chains deal with?
Gamma chains are involved with the Jak/stat pathway
1. Cytokine binds with receptor (like IL-2R) and causes di/trimerization causing autophosphorylation
2. activated JAK will recruit and phosphorylate STAT (=signal transducer and activator of transcription)
3. The phosphorlylation of STAT causes it to dimerize and translocate to the nucleus inititiation transcription
What is Daclizumab?
Also known as Zenapax
-it is an IL-2 blockade, that works by blocking anti-CD25 antibody
-used in acute organ rejection
What is Tofacitinib?
also known as Xeljanz and used in rheumatoid arthritis
-it is a JAK inhibitor that works by inhibitng the common gamma chain-containing cytokine receptors
What are some factors of the extracellular response?
IgG and IgA (B-cells)
-this would be initiated by an extracellular pathogen like bacteria
What are some factors of the intracellular response?
This would be a response to intracellular pathogens like Viruses or intracellular bacteria
-leads to intracellular killing through macrophages (ROI)
-leads to cell destruction with cytotoxic CD8 T cells
What kind of immune response do we need for fungi?
-fungi we need neutrophils and macrophages
What do we need for immune resposne of helminths?
Helminths are parasites
-we need mast cells and IgE (B cells)
What determines the outcome of T cell differentiation and how do T cells know what kind of immune response to mount?
The pathogen will dictate the outcome of T cell differentiation and the DCs will communicate to the T cells based on that pathogen what immune response to mount.
There is an intracellular pathogen, what are the cytokines secreted by the macrophage, what T cell will respond and what are the cytokines it will produce?
In response to intracellular pathogen....
DC will secrete IL-12, IFN-gamma
CD4 will differentiate to Th1
Th1 will produce IFN-gamma, and TNF-alpha
Memorize the shit out of this
Tell me the important things about Memory T cells?
1. They are short lived
2. Found in LN and Peripheral Tissue
3. activated with low concentrations of antigen and without co-stimulation
4. upon activation they differntiate into effector cells.