Ch. 11 Flashcards
Summarize a day in the life of a naive T cell
• After T cells leave the thymus, they enter circulation on an epic journey to find their cognate antigen
o Highly motile, but otherwise boring cells (G0 of the cell cycle, chromatin is condensed, little cytoplasm and little transcriptional activity)
Travel between SLO sites using blood circulation every 12-24 hours
• If t cells scan through and SLO and cannot find their cognate antigen, they simply leave and move on to the next SLO
• However, if they do happen to find an APC presenting their antigen, then IT. IS. ON!
What is Signal 1 of T cell activation?
o The first requirement for T cell activation is antigen recognition via TCR/MHC (& coreceptor) interactions
The low-affinity interactions of MHC/TCR at the contact point between the cells in a region called the central supramolecular activating complex (cSMAC) are stabilized by coreceptors CD4/8 & CD3
• This increases the avidity of the synapse
o Avidity=you can make a strong binding of weak bonds if there are several of them (like h-bonds in water)
What is signal 2 of T cell activation?
o However, even further contact must be made between an APC and a T cell for full activation
Activating coreceptors
• CD28 binding CD80/86
Adhesion molecules in the peripheral supramolecular activating complex (pSMAC)
What is signal 3 of T cell activation?
o However, even further contact must be made between an APC and a T cell for full activation
Activating coreceptors
• CD28 binding CD80/86
Adhesion molecules in the peripheral supramolecular activating complex (pSMAC)
All three signals are necessary, with 1&2 triggering “activation,” and 3 indicated what the cell should differentiate into. What is the response?
In response, IL-2 is produced to trigger cell proliferation
Under what circumstances does clonal anergy result for a T cell?
- result if a costimulatory signal is absent
- this helps provide tolerance (especially in periphery)
- if only signal one is received, the cell is rendered nonresponsive (might happen if a T cell isn’t screened against a peripheral self-antigen during development)
Autocrine signaling of IL-2 has what outcome for an activating T cell?
- IL-2 is an example of an autocrine type of cytokine response system
- T cells produce the cytokine and the receptor for it
- Binding of this ligand induces a very strong proliferation signal during activation stages
What are polarizing cytokines?
cytokines that can send the T cell down different subset developmental pathways
What are superantigens
special class of T-cell activators - viral/bacterial proteins that bind to specific VB regions of TCRs and a chain of class II MHC molecules
Why are superantigens detrimental to our health?
- Specific for the VB
- Any T cell expressing the particular VB chain will be activated
- effectively short-circuits activation by antigen
- activates large numbers
- produces dramatic cytokine secretion by large proportion of inappropriately activated T cells (cytokine storm)
Cytokine storm
DIC, shock, lung injury, cardiac damage, immune paralysis, renal failure
What are the three outcomes of the signaling between a dendritic cell APC and a naive T cell?
- cell survival
- cell cycle entry
- cell differentiation
How many cells can be derived from a single activated naive T cell that has developed into a blast cell? How many days does it take for this population of cells to be formed in an SLO?
1-2 days following activation via interaction with an APC in a T-cell zone of an SLO, T cells will enlarge into a blast cell which starts undergoing repeated rounds of cell divisions
-divide 2-3 times a day for 4-5 days
-2 divisions for 4 days=256 cells
-3 divisions for 5 days=32,768
production of memory and effector clonal cell populations
What is the purpose of an effector CD4+ cell?
CD4+ effectors secrete cytokines to regulate the activity of the other immune cells
- some subtypes stay in SLO to help B cells and generate memory
- others return to sites of infection and enhance activity of phagocytic and cytotoxic cells
What is the purpose of an effector CD8+ T cell?
CD8+ effectors leave lymphoid tissues and circulate to sites of infection, binding and killing infected cells
What are the five main T helper subsets discussed in this section?
TH1, TH2, TH17, TREG, TFH
Describe how an APC dictates which T helper subset a naive T cell should develop into.
- subtype is determined by polarizing cytokines
- APCs may bind PAMPs via PRRs, inducing cytokine secretion
- different PRRs engaged (via different antigens)= different cytokines present
- viruses stimulate IL-12 and IFN-y which induce TH1
- worms stimulate IL-4 and IL-6 which induce TH2 subsets
- different PRRs engaged (via different antigens)= different cytokines present
- APCs may bind PAMPs via PRRs, inducing cytokine secretion
Which T cells regulate cell-mediated immunity?
TH1 and TH17
Which T cells regulate humoral immunity?
TH2 and TFH
Which T cell subsets cross-regulate each other?
- TH1 and TH2 pair
- TH17 and TREG pair
What are the polarizing cytokines, master gene regulator, and effector cytokines of TH1 cells?
- Polarizing cytokines= IL-12, IFN-y, IL-18 (antiviral interferons)
- Master gene regulator= T-Bet
- Effector cytokine= IFN-y and TNF
What are the polarizing cytokines, master gene regulator, and effector cytokines of TH2 cells?
- Polarizing=IL-4
- Master gene regulator= GATA-3
- Effector cytokine= IL-4, IL-5, IL-13
What functions do the effector cytokines of TH1 perform?
- Activates macrophages (stimulates microbicidal activity, MHC II expression)
- Leads to class switching to IgG classes that support phagocytosis, complement fixation, and cytotoxicity
- Supports differentiation of antiviral CD8+ killer T cells due to IFN-y secretion
What functions do the effector cytokines of TH2 perform?
- Activates eosinophils to express IgE receptors
a. When eosinophils bind IgE-tagged pathogens, they release their inflammatory mediators
b. This interaction is also particularly important in allergic reactions - Leads to class switching to IgE/IgG1 classes in B cells, which supports inflammatory mediator release from granulocytes
Suited for extracellular infections and problematic in IgE-mediated allergies
Describe the cross-regulation between TH1 and TH2 cells
• TH1/TH2 subsets are generally inhibitory to each other
• Cytokines can achieve cross-regulation
o IFN-y from TH1 responses inhibits IgE class switching (a common TH2-induced response)
o IL-4 from TH2 responses inhibits production of IgG2a (a common TH1-induced response)
• Master regulators commit T cells to one subset or the other
o T-Bet suppresses TH2 pathway gene expression
o GATA-3 suppresses TH1 pathway gene expression
What are the polarizing cytokines, master gene regulator, and effector cytokines of TH17 cells?
Polarizing cytokines= IL-6 and TGF-B
Master gene regulator= RORyt
Effector cytokines= IL-17A, IL-17F, IL-22
What functions do the effector cytokines of TH17 cells perform?
IL-17A is associated with chronic inflammatory and autoimmune responses
TH17 cells are the dominant inflammatory cell type in chronic autoimmune disorders
• IL-17A may play a role in warding off fungal and extracellular bacterial infections by promoting tissue inflammation
What are the polarizing cytokines, master gene regulator, and effector cytokines of TREG cells?
- Polarizing cytokines=TGF-B and IL-2
- Master gene regulator=FOXP3
- Effector cytokines=IL-10 and TGF-B
What functions do the effector cytokines of TREG cells perform?
IL-10 and TGF-B downregulate inflammation (by inhibiting APCs) and suppress other T-cell subsets
Regulation, suppression of immune and inflammatory responses
Describe the cross-regulation between TH17 and TREG cells
- TGF-B is a key cytokine for differentiation of both subsets
- IL-6 is the “switch,” allowing RORyt to dominate and induce TH17 subset differentiation instead
What are the polarizing cytokines, master gene regulator, and effector cytokines of TFH cells?
- Polarizing cytokines=IL-6 and IL-21
- Master gene regulator=Bcl-6
- Effector cytokines=IL-21 and IL-4
What functions do the effector cytokines of TFH perform?
IL-21 and IL-4 promote B-cell differentiation
Describe the features of TEM cells
o Travel to/between tertiary tissues (skin, lung, liver, intestine, etc.)
o Still committed to a particular T-cell subset
o Contribute better to first-line defenses
Shift right back into effector functions on second Ag exposure
Describe the features of TCM cells
o Reside in/travel between secondary lymphoid tissues
o Live longer/divide more times than TEM cells
o Are rapidly reactivated by second Ag exposure
o Can differentiate into several subset types depending on cytokine environment
How do we tell naive T cells, TEM cells, and TCM cells apart?
o We can differentiate naïve, effector, and memory T cells by differences in surface protein expression
o Three surface markers can differentiate the sets
CD44= an adhesion protein allowing extravasation from blood vessels
CD62L= an adhesion protein
CCR7= a chemokine receptor
