I8 Flashcards
(91 cards)
1
Q
Where does T cell activation occur?
A
exclusively in the secondary lymphoid tissues.
2
Q
Why does T cell activation only occur in secondary lymphoid tissue?
A
This is due to that fact that secondary lymphoid tissues are the only place where there is enough contact between APCs and naïve T cells…remember, there may only be a single T cell in the entire repertoire that has specificity for any particular peptide determinant.
3
Q
What two signals are required for T cell activation?
A
A T cell must recognize its cognate peptide determinant (signal 1) and then receive the costimulatory signal that consist of B7 expressed by the APC binding to CD28 expressed by the T cell (signal 2).
4
Q
T or F. Naïve T cells can only be activated by professional APCs. Why or why not?
A
T, because they are the only cell types that express B7.
5
Q
How do T cells move into secondary lymphoid tissue from the bloodstream?
A
Naïve T cells move into secondary lymphoid tissues by transmigration between the endothelial cells of what are known as high endothelial venules or HEVs. This process is mediated by adhesion molecule interactions.Once T cells occupy a secondary lymphoid tissue, they sample peptide:MHC complexes on the surface of APCs.`
6
Q
What happens to naive T cells that never encounter their cognate determinant in the secondary lymphoid tissue?
A
they will eventually leave the secondary lymphoid tissue via the efferent lymph and travel to another secondary lymphoid tissue.
7
Q
What happens to naive T cells that DO encounter their cognate determinant in the secondary lymphoid tissue?
A
If a naïve T cell encounters its cognate peptide:MHC complex and then receives the needed co-stimulation, the T cell begins to proliferate. The daughter cells then differentiate either into effector cells or memory cells.
8
Q
What are the 4 classes of cell-surface adhesion molecules that are expressed on the surface of host cells (both immune cells and non-immune cells)?
A
1) Selectins2) Mucin-like vascular addressins3) Integrins4) Immunoglobulin superfamily members
9
Q
What are selectins?
A
Lectins that bind to the mucin-like vascular addressins (e.g. CD34, GlyCAM-1, PECAM-1 (CD31))
10
Q
What are Integrins?
A
lymphocyte function associated antigen (LFA-1), VLA-6, alpha-V-beta-3Integrins bind to the immunoglobulin superfamily members.
11
Q
What are the members of the immunoglobulin superfamily?
A
intracellular adhesion molecules (ICAMs), CD2, LFA-3, VCAM-1these bind to integrins
12
Q
Remember that all cell-to-cell interactions are initiated by adhesion molecule interactions and that a genetic deficiency of expression of an adhesion molecule could have very important implications for the immune status of the patient.
A
Remember that all cell-to-cell interactions are initiated by adhesion molecule interactions and that a genetic deficiency of expression of an adhesion molecule could have very important implications for the immune status of the patient.
13
Q
How is the process of naïve T cells entering secondary lymphoid tissue through high endothelial venules mediated by adhesion molecule interactions?
A
L-selectin expressed on the surface of naïve T cells are able to bind to addressins (such as CD34) that are expressed on the surface of HEVs. This initiates the process of T cell migration from the vasculature into the secondary lymphoid tissue
14
Q
L-selectin also has affinity for what other addressin besides CD34?
A
GlyCAM-1, which is also known as sulfated sialyl-Lewis.
15
Q
Describe the entire process of T cell extravasion
A
- Circulating T cell enter the HEV in the lymphoid tissue2. Binding of L-selectin on the T cell surface to GlyCAM-1 and CD34 allow rolling interaction3. Once the T cell is closely associated with the HEV surface, other interactions can occur. Chemokines that are bound to the vascular endothelium can be recognized by chemokine receptors on the surface of the T cell. This results in signaling to the nucleus of the T cell, resulting in activation of the integrins known as LFA-1 on the surface of the T cell.4. Activated LFA-1 binds tightly to ICAM-15. Diapedesis- lymphocyte leaves blood and enters node
16
Q
LFA-1 on T cells is important for the T cell’s ability to interact closely with APCs. How?
A
LFA-1 on T cells is able to bind to ICAM-1 expressed on the surface of APCs. Without this interaction, T cells would not be associated closely enough with APC for MHC:peptide complex sampling by the TCR.
17
Q
Once a T cell has differentiated into an effector cell, how can it be encouraged to enter into inflammatory sites?
A
because it now expresses the integrin known as VLA-4 that can bind to VCAM-1 that is expressed on activated endothelial cells (they become activated when they are in an inflamed tissue).
18
Q
What is E-selectin?
A
is an adhesion molecule from the selectin family that is expressed on vascular endothelial cells that binds to addressins expressed by a variety of leukocytes, including the phagocytes (neutrophils and macrophages), effector T cells, NK cells, and eosinophils.E selectins: Every new kid eventually takes nuestro money
19
Q
Expression of E-selectin on vascular endothelial cells is stimulated by the cytokines ___ and ____.
A
TNF-alpha and IL-1Once E-selectin is expressed on the surface of vascular endothelial cells, addressins expressed on the surface of immune cells bind to E-selectin, initiating the diapedesis process and resulting in accumulation of leukocytes in the inflamed tissue.You may need to know that many tumor cells also express E-selectin ligands, so E-selectin is indirectly involved in tumor metastasis.
20
Q
All 3 APCs express what important molecule on their surface?
A
Costimulator molecule (B7). However, expression of B7 by these cell types is conditional.
21
Q
When do dendritic cells express B7?
A
only express B7 once they have moved into secondary lymphoid tissues
22
Q
When do macrophages and B cells express B7?
A
Both macrophages and B cells express B7 in an inducible manner. If they encounter ligands that bind to their pattern recognition receptors (indicating that there is an infection and an immune response is needed), they will upregulate B7 expression.
23
Q
Which APC is the best for presentation of VIRAL determinants? Why?
A
dendritic cells are the most important APC for presentation of viral determinants.DCs are easily infected by viruses and once infected they are very efficient antigen presenting cells.
24
Q
Which APC is the best for presentation of BACTERIAL determinants? Why?
A
Macrophages are the most important APC for presentation of bacterial determinants because they have many surface PRRs that recognize bacterial surface determinants.B cells can present anything that binds to their surface immunoglobulin component of the B cell receptor. You should be aware that B cells take up antigen primarily via their surface Ig. Once the Ig binds to its cognate determinant, the entire complex is endocytosed and any protein components are processed and presented on MHC molecules (primarily MHC class II).Please be aware that each of these cell types can present antigens derived from any type of pathogen, despite the rules of thumb that I just mentioned.
25
What is the immature form of dendritic cells?
Langerhans's cells. These immature forms dendritic cells populate the tissues underlying all epithelial layers of the body.
26
T or F. Langerhans's cells express B7 molecules on their surface
F. In this form, they do not express B7 molecules and cannot present antigen productively to naïve T cells, but they are very efficient at uptake of antigens. They do express MHC I and II here.
27
What happens when Langerhans cells encounter pathogen antigens?
When they encounter an invading pathogen, they take up antigen, some of which engages PRRs, signaling to the cell that an infection is ongoing and an immune response is needed. The Langerhans's cell then travels via the lymphatics to the draining secondary lymphoid tissue
28
What happens once the Langerhans's cell reaches the secondary lymphoid tissue?
It matures into a fully functional APC. The DC then begins to express high levels of B7 and can very efficiently present antigens to naïve T cells that have specificity for peptides presented on MHC molecules on the DC’s surface.They also have mechanisms for transfer of antigens to other DCs already in the tissue
29
It is critical that you understand where T cell activation occurs...it always occurs in secondary lymphoid tissues, and it is dependent on the T cell receiving B7 co-stimulation that can only be supplied by a professional APC.
It is critical that you understand where T cell activation occurs...it always occurs in secondary lymphoid tissues, and it is dependent on the T cell receiving B7 co-stimulation that can only be supplied by a professional APC.
30
What is the (very) general basis of cross-presentation mechanisms?
The MHC class I pathway and how peptides derived from proteins that were in the cytoplasm of the cell are trafficked into the MHC class I pathway. I have also talked about the MHC class II pathway and how peptide derived from proteins taken up from the extracellular milieu are presented primarily through the MHC class II pathway. However, it is important for you to recognize that some peptides derived from intracellular pathogens will be presented through the MHC class II pathway and some peptides derived from extracellular pathogens will be presented via the MHC class I pathway. The mechanisms are complex.. don't need to know for Step 1
31
What type of MHC molecule and CD molecule would usually be used in the presentation of extracellular bacteria?
MHC class II and CD4
32
What type of MHC molecule and CD molecule would usually be used in the presentation of viruses?
MHC class I and CD8 (think intracellular)
33
What kinds of surface receptors can be seen on the surface of an immature dendritic cell (Langerhans cell)?
These cells express both MHC class I and MHC class II and they express several adhesion molecules (LFA-1, ICAM-1, and LFA-3 or CD58). Another surface marker that is shown here is complement receptor 4 that allows DCs to recognize antibody-opsonized foreign materials, facilitating uptake for processing and presentation. There are also a couple of surface pattern recognition receptors indicated (DC-SIGN and DEC 205). There are many others that are not included here.I do not expect you to memorize any of these, but instead want you to remember that adhesion molecules are critical to the function of all immune cells, that the professional antigen presenting cells all express both MHC class I and MHC class II as well as B7 molecules, but that the expression level of each of these is increased dramatically when the APC has determined that an immune response is needed (due to PRR engagement). As you see here, this immature tissue DC does not express B7 molecules.
34
What differences in the types/amount of surface receptors can be seen on the surface of a mature dendritic cell after it has made its way into a lymphoid tissue?
A mature DC moves into a secondary lymphoid tissue because it detected some type of pathogenic insult. The most important differences that you should recognize are: (1) mature DCs express high levels of B7 molecules on their surface, enabling them to productively present peptide determinants to naïve T cells, and (2) they upregulate expression of both MHC class I and MHC class II so that they can more efficiently present peptides to T cells.
35
What is DC-CK?
Mature DCs produce DC-CK, a chemotactic factor for naïve T cells. This increases the rate of T cell sampling of the MHC:peptide complexes on the surface of the DC.
36
How do B cell take up antigens for processing and presentation to T cells?
Each B cell expresses many copies of its BCR, and each copy has an identical immunoglobulin component that can recognize a specific antigenic determinant. If the B cell encounters its cognate determinant, the BCR:antigen complex is endocytosed and the protein components of that entire complex are proteolytically processed. Peptides derived from that processing are then loaded onto MHC molecules (primarily MHC class II) that are then transported to the surface of the B cell for display.
37
B cells that have ingested an antigen:BCR complex and expressed an MHC molecule (mostly MHC class II) can present the molecule to what kind of cells?
The B cell can present peptides to either naïve T cells (either CD4+ or CD8+) or effector CD4+ T cells.
38
What happens if an effector CD4+ T cell recognizes its cognate peptide:MHC class II complex on the surface of a B cell?
it will supply the second signal of activation to the B cell, resulting in B cell activation. This does not require recognition of B7 molecules on the B cell surface by the CD4+ effector cell because effector T cells do not require costimulation to perform their effector function.
39
What happens if the B cell has encountered PAMP(s) via its PRRs (as opposed to encountering an antigen via its BCR)?
it will upregulate B7 molecules. A B cell that has done this can productively present peptides to naïve CD4+ or CD8+ T cells.
40
Macrophages are also professional APCs and in their unactivated form that are very similar to immature dendritic cells with respect to their lack of ability to productively present peptides to naïve T cells. When they recognize PAMP(s) via their PRRs, they upregulate expression of B7 as well as MHC class I and MHC class II and they become very efficient APCs.As we will discuss in further detail in a later lecture, some helper T cells can activate macrophages to a level significantly higher than PRR engagement can, making them an even more efficient APCs.
Macrophages are also professional APCs and in their unactivated form that are very similar to immature dendritic cells with respect to their lack of ability to productively present peptides to naïve T cells. When they recognize PAMP(s) via their PRRs, they upregulate expression of B7 as well as MHC class I and MHC class II and they become very efficient APCs.As we will discuss in further detail in a later lecture, some helper T cells can activate macrophages to a level significantly higher than PRR engagement can, making them an even more efficient APCs.
41
Is LFA-1 expressed on the surface of naïve T cells, effector T cells, or both?
BOTH.
42
What is the significance of LFA-1 being expressed on ALL T cells (naive and effector)?
LFA-1 binds to ICAMs that are expressed on the surface of APCs. This adhesion molecule interaction brings naïve T cells in close enough proximity to the APC that either CD4 or CD8 can bind to MHC class II or MHC class I, respectively. Once that interaction occurs, peptide sampling by the TCR can occur.Without the initial interaction between LFA-1 and ICAMs, the T cell would be unable to efficiently sample peptide bound to MHC molecules.
43
What is the firsts step in binding between APCs and T cells (naive OR effector)?
The initial interaction between T cells and dendritic cells is mediated by LFA-1 expressed by the T cell binding to ICAM-1 on the surface of the DC.
44
What happens after successful binding of LFA-1 on the T cell to ICAM-1 on the APC?
The TCR co-receptor (CD4 or CD8) is then brought in close enough proximity to the DC that it can bind to MHC class II. This facilitates TCR sampling of the peptide bound in the binding groove of the MHC molecule and tightens the interaction between the two cells by sending signals that cause an alteration in the conformation of LFA-1.The conformational change to LFA-1 increases its affinity for ICAM-1, tightening the interactions between the two cells, allowing the TCR to thoroughly sample the MHC:peptide complex.
45
T or F. There is a single copy of each of the adhesion molecules, the TCR, the MHC class II molecule.
F...in reality, there are a large number of each of these surface markers on every cell.
46
Is the binding of LFA-1 to ICAM-1 reversible or irreversible? Why to either response?
The affinity of the various adhesion molecule interactions are not very high, so the binding of any LFA-1 molecule to ICAM-1 is easily reversible. However, since there are many copies of these molecules on the surface of each cell, their combined binding strength (or avidity) is much higher than any single copy’s affinity. Once LFA-1 has been signaled to undergo a conformational change, its affinity for ICAM-1 is significantly higher. I would guess that it is somewhere between 2 and 10-fold higher than it is original conformation. The affinity of CD4 for MHC class II molecules is likely similar to that of the average adhesion molecule interaction, or maybe a little higher. **The affinity of the T cell receptor for its cognate peptide determinant is many orders of magnitude higher than the other interactions that have been discussed on this slide.**
47
What is the first of the two signals that must be received for a T cell to become activated?
The first of those signals is recognition of cognate peptide determinant by the TCR. You must remember that T cells are MHC-restricted, meaning that they can only recognize peptide bound to MHC molecules. When the TCR recognizes the peptide it is sampling with high affinity, a signal is transmitted to the T cell nucleus through the CD3 complex. This is the first signal of T cell activation.This can only occur if LFA-1/ICAM binding is successful
48
T or F. A single copy of the TCR recognizing its cognate peptide is sufficient to supply enough signaling for this 1st activation signal to be received.
F. There is a threshold of signaling that is required, and that threshold requires multiple copies (not sure how many) of the TCR to recognize their respective cognate determinant.
49
What is the second signal that must be received for a T cell to become activated?
2nd Activation Signal: The second signal of activation is costimulation: if the T cell recognizes B7 molecules on the surface of the APC via its binding to CD28 on the T cell, the second signal is received and the T cell becomes activated. This is why professional antigen presenting cells must express B7 for them to be able to productively present antigen to naïve T cells.***Again, there is a threshold level of costimulatory signaling that is required for a naïve T cell to become activated.
50
What is the first thing that happens once a T cell becomes activated?
The first thing that happens is that T cell begins to proliferate (make new copies of itself). Another term for this is clonal expansion. A T cell that has specificity for a peptide derived from a foreign invader has been identified and activated, so now it must clonally expand so that there will be many copies of the T cell in the repertoire. Remember that in your entire repertoire of naïve T cells there are likely to be no more than a few copies of any T cell with the same specificity for antigen. Many copies of any clonal line of T cell are required to mount an effective acquired immune response.
51
What two important changes that take place in a T cell once it becomes activated?
1. It begins to secrete the T cell growth factor known as interleukin-2 (or IL-2).2. It begins to produce a high affinity form of the IL-2 receptor so that it can optimally respond to IL-2 signaling
52
What does IL-2 do?
When IL-2 binds to the IL-2 receptor on a T cell, it drives proliferation and eventual differentiation of that T cell. IL-2 is an autocrine growth factor because T cells make both the IL-2 and its receptor. So, the IL-2 produced by an activated T cell can bind to IL-2 receptors on that same T cell, driving proliferation of that T cell.
53
T or F. All resting naïve T cells express a low-affinity form of the IL-2 receptor
T.
54
Describe the composition of a IL-2 receptor on a resting (non-activated) T cell.
consists of two of the three polypeptide chains that form the IL-2 receptor (the γ- and β-chains). IL-2 can bind to this low affinity receptor, resulting in signaling through the receptor. However, much higher concentrations of IL-2 are required than if the receptor also included its other chain.Once the IL-2 concentration is high enough to initiate signaling through the low affinity IL-2 receptor, the T cell will begin to express the alpha chain of the IL-2 receptor and will soon express the high affinity IL-2 receptor on its surface
55
Describe the composition of a IL-2 receptor on an activated T cell.
Once a T cell becomes activated, it begins to express the third chain of the the IL-2 receptor (the α-chain). Once a T cell expresses the high affinity heterotrimeric IL-2 receptor, much lower quantities of IL-2 are required to drive proliferation of that T cell.Note that this "high affinity" IL-2 receptor can be activated via a large stimulation of the low-affinity IL-2 receptor or via activation of the T cell through binding of B7 to CD28 and TCR binding to its antigen on an APC MHC molecule
56
T or F. IL-2 drives proliferation of the activated T cell, resulting in clonal expansion of that specific T cell.
T. All daughter cells will have the same antigen specificity as the original naïve T cell.IL-2 is a critical T cell growth factor. You will no doubt be required to recognize that a genetic deficiency of either IL-2 or one of the two chains of the low affinity IL-2 receptor (beta and gamma) would result in the patient having no ability to produce an effector T cell response. As you will learn later, this results in what is known as severe combine immunodeficiency, or SCID.
57
What is Peripheral tolerance?
the immune system is designed so that self-reactive T cells that (through error) complete thymic development and become members of the T cell repertoire can later be identified as self-reactive and removed from the repertoire. Once a naïve T cell has received its first signal of activation (recognition of cognate antigen), it must receive the B7 costimulation signal very soon, or it will become anergic and die via programmed cell death (apoptosis). Because the three professional APCs only express B7 when they have detected an infection, in the absence of infection, naïve T cells that recognize their cognate determinant will not receive co-stimulation and will be clonally deleted.This backup mechanism prevents most self-reactive T cells from ever becoming activated, and actually results in removal of many of them from the repertoire.
58
T or F. B7 binding to CD28 in the absence of the 1st signal of activation will cause T cell activation.
F. B7 binding to CD28 in the absence of the 1st signal of activation will have absolutely no impact on the T cells.However, if a naïve T cell recognizes its cognate peptide determinant presented on an APC that expresses B7, that T cell receives both signals of activation and begins to proliferate and differentiate.
59
Another look at peripheral tolerance.
Example: A naïve T cell has recognized its cognate peptide determinant presented on an antigen presenting cell in the secondary lymphoid tissue. However, the APC does not express B7 molecules, so the T cell does not receive co-stimulation signaling. When this occurs, the T cell becomes anergic and dies soon thereafter. This is known as peripheral tolerance. If an APC presents an antigen but has not been stimulated to up regulate B7 expression... meaning no PRRs have recognized PAMPS, indicating that there is no infection... The T cell is likely recognizing a self-derived peptide determinant. Peripheral tolerance allows the immune system to identify many self-reactive T cells in this way and to remove them from the T cell repertoire to prevent eventual development of autoimmune disease. Quick think: Which of the APC types are most likely to participate in peripheral tolerance?
60
T or F. B7 expression is inducible on each of the APC types.
T.
61
Describe the (assumed) basis of many autoimmune disease via macrophage activation
Left-Hand Panels: In the left hand panel, you see a macrophage that is taking up some non-bacterial protein (and you can assume that the protein is not derived from any pathogen because it is not recognized by any PRR). This macrophage has no reason to upregulate B7 expression, so any naïve T cell that recognizes its cognate determinant on this macrophage will never receive co-stimulation and will become anergic and die.Middle Panels: In this panel a macrophage takes up bacteria that are recognized by PRRs, resulting in B7 expression by the macrophage. It can now productively present peptide determinants to naïve T cells, resulting in their activation.Right-Hand Panels: Here is the key panel: The macrophage is taking up both bacteria and a protein that IS NOT derived from any pathogen. Because the macrophage will recognize the bacteria via its PRRs, it will upregulate B7 expression and will be able to productively present antigens to naïve T cells. Because a macrophage processes and presents all proteins that it takes up, peptides derived from both the bacterium and the red protein (which for argument sake is a self protein) will be processed and their peptides will be loaded onto MHC molecules. If a naïve T cell that has specificity for a peptide derived from the red self protein recognizes its cognate peptide on that macrophage, it will receive costimulation and will become activated. It is believed that most autoimmune diseases are initiated during infections with a pathogen. Encounter with the pathogen results in B7 upregulation on APCs, allowing them to productively present self peptides to self-reactive T cells (in addition to pathogen-derived peptides to other naïve T cells).Many vaccines include pathogen-derived PAMPs that are used to induce upregulation of B7 expression by APC so that the vaccine immunogen can be productively presented to naïve T cells. The immune system has to be “faked out” so that it will make an immune response to the vaccine immunogen.
62
T or F. The activation signaling requirement (IL-2) for CD8+ T cells is significantly higher than for CD4+ T cells.
T. The is a built-in regulatory fail-safe of the immune system
63
Which APCs express the highest concentration of B7 on the surface of any of the APCs?
Dendritic cells. In fact, their B7 density once they reside in a secondary lymphoid tissue is so high that dendritic cells can productively present antigen to naïve CD8+ T cells with no assistance.Activated CD8 T cells make IL-2, driving its own proliferation and differentiation
64
Mature dendritic cells can activate naive CD8 T cells without help due to high levels of B7 expression on their surface. Macrophages and B cells, however, express lower levels of B7 than a mature dendritic cell. For a naïve CD8+ T cell to be activated by one of these APC types, they require some help. How does this work?
An effector TH1 CD4+ T cell bind to its cognate determinant bound to an adjacent MHC class II molecule on the macrophage surface. One of the effector mechanisms of this helper T cell is to activate macrophages. This type of activation can cause enough upregulation of B7 expression that a CD8+ T cell (bound at the same time) can be activated.OR!!!In this case, an adjacent naïve CD4+ T cell has received its two signals of activation and is producing IL-2. Because the naïve CD8+ T cell is so close by, some of that IL-2 binds to its IL-2 receptors, decreasing the threshold for its two activation signals. This allows the CD8+ T cell to be activated even though the APC does not express very high density of B7.
65
What is an effector T cell?
An effector T cell is a fully differentiated T cell that is poised to perform its effector function. Effector T cells no longer require B7 costimulation. When they encounter their cognate determinant bound to an MHC molecule, they perform their effector function.Effector T cells also express a different array of adhesion molecules that direct them to the appropriate tissues in the body and allow them to interact with the appropriate cell types..
66
What is the only effector CD8 T cell type and what do they do?
They are known as cytotoxic T cells or cytotoxic T lymphocytes (CTLs). This is the effector cell of the acquired immune response that is most responsible for limiting virus infections by recognizing and killing infected cells.
67
There are several CD4+ effector T cell types, two of which are ___ and ____.
TH1 and TH2 T cells
68
Why are CD4+ effector T cells known as T helper cells?
Because their effector functions are to produce cytokines and chemokines that modulate the function of other cell types.
69
During an intracellular infection (such as a viral infection), the predominant T helper type that will be generated is the ____.
TH1 (or T helper type 1) cell type. These helper cells promote immune responses that are most effective for clearance of intracellular infections (cell-mediated responses).
70
During an extracellular infection, the predominant T helper type that will be generated is the ____.
TH2 (or T helper type 2) cell type. These helper cells promote immune responses that are most effective for clearance of extracellular infections (antibody responses).
71
Two of the most important functions of both of the helper cell types are: 
1) supplying the second signals of B cell activation. 2) Both cell types also modulate the activity of macrophages. TH1 cells activate macrophages, making them better killers of bacteria they have taken up. TH2 cells actually down-regulate the activity of macrophages.
72
What happens when a naive T cell becomes activated?
When a naive T cell becomes activated, it begins to proliferate and differentiate and form immature effector (TH0) T cells. The primary factor that drives their differentiation is the cytokine milieu during their differentiation. Once they have differentiated into an effector cell type, they then produce a specific set of cytokines and chemokines that promote the appropriate type of acquired response for removal of the pathogen.
73
TH1 T helper cells express what two primary cytokines in high quantities and what does each do?
IL-2 and IFN- gamma. The IL-2 helps to promote activation of CD8+ T cells by reducing their activation signaling requirements, while IFN-γ is a potent activator of macrophages.
74
What else do TH1 helper T cells do?
These helper cells also produce other cytokines that help to drive class switching of B cell that they help to activate. They promote class switching to antibody isotypes that are best for clearance of intracellular pathogens (the one mentioned here is IgG1), and important opsonins for activating NK cells to perform ADCC that results in killing of infected cells.
75
What do TH2 helper T cells do?
make a different array of cytokines (IL-4 and IL-5 are most notable) that promote class switching to neutralizing antibody isotypes, secretory antibody (IgA) and mast cell activating antibody (IgE). All of these are important for clearance of extracellular pathogens.
76
The cytokines that promote TH0 to TH1 differentiation are __ and __.
IL-12 and IFN-gamma.
77
The cytokines that promote TH0 to TH2 differentiation are __, __, __, and __. Which is most important?
IL-4, IL-5, IL-6, and IL-10 (IL-4 is most important).
78
How is IL-12 produced?
Intracellular infections induce IL-12 production by APCs. Dendritic cells are shown here, but macrophages also produce IL-12 when infected with an intracellular pathogen. In turn, IL-12 (in combination with other cytokines) induce production of IFN-gamma by NK cells, γδ T cells, and potentially other cell types. IFN-gamma is the direct trigger that promotes TH1 differentiation.
79
What is an important source of IL-4 that promotes differentiation toward a TH2 phenotype?
NK T cells (other pathogens such as worms may induce this)
80
Cytokines are not the only factors that promote T helper differentiation. What else does?
1) Affinity of the TCR for its cognate determinant appears to also play a role. Mechanism not clear.2) The concentration of the cognate determinant however is more logical. During an intracellular infection, viruses use the host protein production machinery to reproduce its proteins while bacteria replicate in the cytoplasm. This leads to a high concentration of pathogen-derived proteins in the cytoplasm. Because these proteins will be processed by the proteosome and then transported into the ER for MHC loading and because they are in high supply, there will be a relatively high concentration. It makes sense that high antigen concentration leads to TH1 development.During an extracellular infection, the pathogen is replicating in extracellular spaces and their antigens must be taken up by APCs for presentation. The amount of antigen that will be used to generate peptide for loading onto MHC is therefore much lower than in an intracellular infection. It makes sense then that TH2 differentiation is favored in this case.
81
What is a Treg cell?
These cells play a critical role in self tolerance of the T cell population by suppressing activation of T cells to self-determinants. Unlike T helper 1 and T helper 2 cells, Tregs differentiate from TH0 during thymic development in the medulla during negative selection.
82
Tregs have a large TCR repertoire that is biased toward self-determinants, and they produce two powerful anti-inflammatory cytokines:
TGF-beta (the most potent) and IL-10.
83
Expression of the TGF-beta and IL-10 by Treg cells is driven by the transcription factor ___.
FoxP3
84
During negative selection, it appears that many of the self-reactive T cells that are identified are signaled to differentiate into Treg cells instead of undergoing apoptotic death. It is believed that the Hassall’s corpuscles found in the thymic medulla play an important role in this by producing a cytokine known as ___. What does this cytokine do?
TSLP. Acts on medullary dendritic cells, causing them to upregulate B7 expression and production of various cytokines (one might be TGF-beta). Some of the self-reactive CD4+ T cells are driven to differentiate into Treg cells and leave the thymus.
85
Tregs sample MHC peptide complexes in the secondary lymphoid tissues, and if they recognize their cognate determinant (which is most likely self- derived) they produce TGF-β and IL-10. These cytokines down-regulate activation of other T cells that are sampling peptides on that same APC. This will certainly prevent activation of some T cells that are specific for pathogen-derived peptides, but it will also prevent the activation of many self-reactive T cell
Tregs sample MHC peptide complexes in the secondary lymphoid tissues, and if they recognize their cognate determinant (which is most likely self- derived) they produce TGF-β and IL-10. These cytokines down-regulate activation of other T cells that are sampling peptides on that same APC. This will certainly prevent activation of some T cells that are specific for pathogen-derived peptides, but it will also prevent the activation of many self-reactive T cell
86
T helper cell produce cytokines that promote differentiation of newly proliferating CD4 T cells toward like phenotypes. Examples?
As an example, TH1 cells produce large quantities of IFN- gamma, a cytokine that drives differentiation of TH0 cells toward TH1.Likewise, TH2 cells produce cytokines (IL-4 and IL-10) that promote TH0 cell differentiation toward the TH2 phenotype.Tregs on the other hand produce the anti-inflammatory cytokine TGF-beta that suppresses activation and differentiation of T cells.
87
What is the transcription factor that predominantly drives expression of cytokines in TH1 cells?
T-bet
88
What is the transcription factor that predominantly drives expression of cytokines in TH2 cells?
GATA-3
89
What is the transcription factor that predominantly drives expression of cytokines in Treg cells?
FoxP3. This is the one you are most likely to be asked about on exams and step
90
What do T helper 17 cells do?
They are pro-inflammatory cell types that are involved in anti-microbial immunity at epithelial-mucosal barriersThe primary thing that you need to know about these cells is that they produce IL-17, a potent neutrophil recruiter/activator. They also produce IL-22, a cytokine that stimulates antimicrobial peptide production by epithelial cells.
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Differentiation of TH0 into TH17 cells is driven by which cytokines?
TGF-B, IL-6, IL-21, and IL-23 (still being researched)
