How are the T cells activated
They are activated by TCR, coreceptors (that bind to ligands) and cytokines
How are Naive T cells activated
1. They move from lymph node to lymph node via blood 2. In the lymph node they look for dendritic cells, they literally crawl over a dendritic cell and see if it is presenting an antigen 3. If an antigen is presented the T cell binds to the antigen and this leads to clonal expansion
What T cells does the dendritic cells stimulate and what happens to the T cells next
1. Stimulate both CD4 and CD8 T cells 2. They undergo proliferation and differentiation 3. T cells exit the lymph node through the blood stream and go to the site of infection
How does TCR lead to development of a signal cascade after it binds to an antigen
It has accessory molecules associated with which are a dimer of CD3epsiolon-gamma and CD3epsiolon-delta and a homodimer of zeta chain. The TCR itself has a very short intramembrane domain so it cannot lead to singal cascade by itself.
The zeta chain are actually the ones that do the work for signal cascade
Explain the mechanism of action in detail for T cell activation
When a dendritic cell presents an antigen to a T cell, the T cell remains bound to the dendritic cell for a long period of time. However, it is known that the affinity TCR with antigen on MHC is very low and it alone cannot account for the binding of the two cells. Other molecules that are involved here are:
1. CD4 or CD8 proteins also bind to the MHC increasing its affinity
2. Coreceptors come in to play here, the most common one being CD28 that binds to B7-1/2 (aka CD80/CD86)
3. The greatest increase in affinity comes from ICAM-1s expressed on denritic cells that bind with LFA-1s expressed on T cells
What are some of the important co receptors and what are their properties
1. CD4, they bind to MHC class II only, MHC class II are present on APCs which are B cells, macrophages and dendritic cells
2. CD8, binds to MHC I, present in all nucleated cells
3. CD28, binds to B7-1/2, presented by APCs: macrophages, dendritic cells and B cells
4. LFA-1, binds to ICAM-1, presented by Endothelial, fibroblast, macrophages and dendritic cells
What is LFA-1 made of
It is a dimer of CD11a and CD18
What are some of the other receptors we should know about
1. CD25, it is part of the IL-2 ligands so it binds with IL-2. It is expressed by all T cells
2. CD154, it is also called CD40L so it binds to CD40. It is expressed by APCs:macrophages, denritic cells and B cells
Immunological check points
Explain the TCR signaling pathway
1. TCR ligation
2. Phosphorylation of ITAMs by Lck = Immunological Tyrosine-based Activation Motifs AND Lymphocyte specific protein tyrosine Kinase
3. Recruitment and activation of ZAP70 binding to the zeta chains
4. Phospholipase C gamma (PLCgamma) makes DAG and IP3.
5. DAG activates NFkappaB and IP3 activates NF-AT
6. ZAP70 also leads to MAPK activation leading to AP-1 activation
When NF-AT is p's it stays in the cytoplasm, when it is dep's it is activated and goes into the nucleus.
1. PLC makes IP3
2. IP3 bind to IP3 receptors on ER and released Ca
3. Ca binds to calmodulin that activates an enzyme called Calcineurin which catalyzes the dep's of NF-AT to activate it.
IMPORTANT: 2 drugs that inhibit Calcineurin are Cyclosporin and Tacrolimus. They are used in transplants.
What are induced by the 3 pathways of T cells
1. NFkappaB induces formation of IL-2, IFNgamma and TNFalpha
2. NF-AT induces formation of IL-2, IL-4, IFNgamma and TNFalpha
3. AP-1 induces formation of IL-2
What is another pathway that is not well understood but important in T cell mediated immune response
The mTOR pathway:
1. PI3-K activates Akt
2. Akt activates(?) mTOR
3. mTOR increases protein translation
Siromilus (rapamycin) inhibits mTOR and doesnt allow the cell to advance from G1 phase
What is the cytokine that is required for T cell activation
What are the drugs that can regulate immunologic checkpoints
3. Abatacept is a drug that is a CTLA4-Ig fused together. It binds to CTLA4 and turns off the T cells. This drug is used in autoimmune diseases such as reuhmatoid arthritis.
Where does the cytokine come from for T cell activation
Paracrine - APC and autocrine - IL2
What is the structure of IL-2
It is a trimer, it consists of an alpha chain, beta chain and a common gamma chain (this common gamma chain is shared by an entire class of cytokines).
IL2Ralpha is also called CD25.
What is the signaling pathway shared by this family of cytokines
Drugs that inhibit this pathway and their uses
1. Daclizumba (Zenapax) - blocks CD25, it is an antibody, acute organ rejection
2. Tofacitinib (Xeljanz) - JAK inhibitor, rhematoid arthritis, inhibits common gamma chain pathways
What kind of specific response is required for different pathogens
1. Extracellular bacteria: IgA, IgG, complement and neutrophils
2. Intracellular pathogens (virus and bacteria): Intercellular killing, macrophages, CD8 Cells
3. Fungi: neutrophils and macrophages
4. Helminths: Mast cells and IgE (B cells)
These are the different classes of CD4 cells. It is important to know that we cant have a fine distinction in the immune response for different pathogens and often an adaptive immune response organized by CD4 cells is a combination of several differently classified immune response that are shown in the diagram
This is what the CD4 T cells differentiate into.
The folicular helper T cells dont make any cytokines but rather they go to the lymph nodes and aid in B cells activation and function in adaptive immune response
How does the CD4 T cells know what to differentiate into
They take orders from dendritic cells which in turn get the required signals from PAMPs. So really the pathogen itself drives the specific immune response
Describe the properties of Memory T cells
1. They're the only T cells that remain after the pathogen has been completely removed
2. They're found in the lymph nodes and in the peripheral tissues, they wander around doing whatever they want to do
3. They get activated when they encounter the same pathogen, they DO NOT NEED COSTIMULATION.
4. Upon activation they themselves differentiate into effector T cells