Immunology Unit 3 - Chapter 10 T-Cell Activation, Helper Subset Differentiation, and Memory
what is Immunologic memory?
In the final few slides, let's focus on memory T cells, which obviously participate in immunologic memory. Immunologic memory is defined as the ability of the immune system to respond much more swiftly and with greater efficiency during a second exposure to the same pathogen.
Memory or effector T cells might remain in the lymph node or circulate to different sites. What happens to CD8+ cytotoxic cells? what about CD4+ cells?
•CD8+ cytotoxic T cells leave the secondary lymphoid tissues and circulate to sites of infection, where they bind and kill infected cells •CD4+ helper T cells secrete cytokines that orchestrate the activity of several other cell types, including B cells, macrophages, and other T cells •Some CD4+ T cells, particularly those that help B cells and those that become central memory T cells, stay within the secondary lymphoid tissue •Other CD4+ T cells return to the sites of infection and enhance the activity of macrophages and cytotoxic cells •Another subset might circulate to other tissues to join the first lines of attack against re-infection.
How do helper T cells actually provide help? Let's summarize:
•Helper T cells can provide direct, cognate help to B cells and influence their differentiation via expression of CD40L and the secretion of effector cytokines. •Helper T cells can provide indirect help to CTLs and other neighboring immune cells by interacting with APCs and producing cytokines that influence cytotoxic and inflammatory activity of multiple cell types. •Different helper T-cell subsets deliver effector cytokines that are tailored to the pathogen that initiated the immune response. •Helper T-cell subsets can also exacerbate inflammatory diseases and can participate in autoimmunity and allergy - The development of lepromatous or tuberculoid leprosy depends, in part, on the balance between TH1 and TH2 responses. In tuberculoid leprosy, the immune response is characterized by a TH1-type response and high circulating levels of IL-2, IFN-γ, and lymphotoxin-α (LT-α). In lepromatous leprosy, there is a TH2-type immune response, with high circulating levels of IL-4 and IL-5. IL-10 is also produced and may come from other helper subsets, including TREG cells. This cytokine profile explains the diminished cell-mediated immunity and increased production of serum antibody in lepromatous leprosy. SO the type of helper t cell is also linked to the quality of the immune response and the progression of certain diseases
We now distinguish four broad subsets of memory T cells: stem cell memory T cells (TSCM), central memory T cells (TCM), effector memory T cells (TEM), and resident memory T cells (TRM). These differ in location, phenotype, and function. Recent work has also revealed a great deal of diversity within these subsets, whose relationships are still being clarified (in other words, there is still a great deal of unknown about memory T cells). What are TCM cells - central memory T cells?
•Reside in/travel between secondary lymphoid tissues •Live longer/divide more times than TEM cells •Are rapidly reactivated by second antigen exposure •Can differentiate into several subset types depending on cytokine environment
what are the main roles of the following T helper cells: TH1, TH2, TH17, TREG, and TFH?
•TH1 regulate immunity to intracellular bacteria and viruses •TH2 (and perhaps TH9) regulate immunity to worms •TH17 regulate immunity to extracellular bacteria and fungi •TREG are inhibitory in terminating immune responses and inhibiting autoimmunity •TFH regulate humoral immunity (B cells) Each produces a distinct cytokine profile and regulates distinct activities within the body. We will look at these cells in more details in the next few slides.
A successful T cell-APC interaction results in the stable organization of signaling molecules into an _______ __________. What are the two parts?
A successful T cell-APC interaction results in the stable organization of signaling molecules into an immune synapse. There are two parts: •central supramolecular activating complex, or cSMAC •peripheral supramolecular activating complex, or pSMAC Signal 1 is transmitting through the cSMAC while pSMAC is there to stabilize and keep the interaction going. The TCR/MHC-peptide complexes, which deliver Signal 1, aggregate in the cSMAC. The intrinsic affinity between the TCR and MHC-peptide surfaces is actually quite low (Kd ranges from 10-4 M to 10-7 M). Signal 1, in fact, is stabilized by the activity of several other molecules, which together increase the avidity (the combined affinity of all cell-cell interactions) of the cellular interaction. Adhesion molecules and their ligands (e.g., LFA-1/ICAM-1 and LFA-3/CD2) organize themselves around the perimeter of the central aggregate, forming the pSMAC. Interactions between these molecules help to sustain the signals generated by allowing long-term cell interactions. In the cSMAC you find the T cell receptor, the Lck kinase, and CD4 (this stuff is basically signal 1). The t cell is binding to its MHC partner at the center of the ring. In this case, we have an MHC class II antigen which comes from the exogenous pathway and in MHC class I the antigen comes from the endogenous pathway BUT there is still a question of why the interactions at the center is not enough? Well it turns out that the affinity between these complexes is fairly low. SO this is where the pSMAC comes in handy. In the pSMAC you find molecules (LFA/ICAM and FA-3/CD2) which are providing additional interactions to maintain the binding of the T cell to the APC for an extended period of time - this allows for continuous T cell signaling process SO OVERALL the pSMAC is involved in maintaining the interaction while cSMAC is the signaling part which comes from the t cell receptor through CD8 and Lck
Where does T cell activation take place and what does it result in? Does activation require a single or several receptor-ligand interactions? What else does it require? Once activated what do CD4+ cells become? What about CD8+?
Activation of a naïve T cell in the secondary lymphoid tissues results in the generation of effector and memory T cells. Activation requires several receptor-ligand interactions between the T cell and a dendritic cell, as well as signals through cytokines produced by the activating APC as well as other supportive cells in the lymphoid organ. CD4+ T cells become effector helper T cells (TH) and secrete cytokines that enhance the activity of many other immune cells. CD8+ T cells become cytotoxic T cells (TC) that kill infected cells. (more on this in chapter 12) SO once a naïve T cell is selected it will travel to a secondary lymph organ - like a lymph node - to be activated. An APC presenting MHC class II peptides can bind to a NaÏve CD4+ T cell. If it is the correct antigen then that T cell is activated. But keep in mind that CD4+ activated T cells aren't the ones doing the killing - but rather they are more like an assistant and thy are involved in activating B cells and memory For CD8+ we have a similar process but upon activation we get cytotoxic effector T cells that can kill. Also remember that MHC Class II is on APCs while MHC class I is on nucleated cells. also that while although dendritic cells are considered nucleated they still express MHC class II and MHC class I
Which cells are capable of providing both Signal 1 and Signal 2 to a naïve T cell?
Although almost all cells in the body express MHC class I, only professional APCs (dendritic cells, activated macrophages, and activated B cells) express the high levels of MHC class II molecules that are required for naïve CD4+ T-cell activation. Professional APCs are also capable of expressing costimulatory ligands. In order to initiate a T-cell response, all professional APCs must first be activated by microbial components via their pattern recognition receptors (PRRs). This encounter enhances antigen presentation activity, and up-regulates expression of MHC and costimulatory ligands.
What regulates the differentiation of T-cells into distinct helper subsets?
Appropriate signals are provided by polarizing cytokines. Interaction of pathogen with pattern recognition receptors (PRRs) on dendritic cells and other neighboring immune cells determines which polarizing cytokines are produced and, hence, into which T helper subset a naïve T cell will differentiate. In general, polarizing cytokines that arise from dendritic cells or other neighboring cells interact with cytokine receptors and generate signals that induce transcription of unique master gene regulators. These master regulators, in turn, regulate expression of various genes, including effector cytokines, which define the function of each subset. So, as we will see, each of the major T helper cell subsets is characterized by (1) a distinct set of polarizing cytokines that induce the expression of (2) a master gene regulator that regulates expression of (3) a signature set of effector cytokines the T-cell population produces once it is fully differentiated. SO when you think about the effect of T helper cell activation you need to think of the polarizing cytokine (so the signal that arrives at the cell) --> the effect which is the activation of a master gene regulator --> and end result being the secretion of an effector cytokine
CD4+ and CD8+ cells leave the thymus and enter the circulation as? What occurs if a naïve T cell does not encounter an antigen to which it is specific for? Vise vera?
CD4+ and CD8+ T cells leave the thymus and enter the circulation as naïve T cells. Although relatively mature, they have not yet encountered antigen. They exhibit little transcriptional activity. However, they are mobile cells and recirculate continually among the blood, lymph, and secondary lymphoid tissues, including the lymph nodes, browsing for antigen. It is estimated that each naïve T cell recirculates from blood through lymph nodes and back again every 12 to 24 hours. Because only about 1 in 105 naïve T cells is likely to be specific for any given antigen, this large-scale recirculation increases the chances that a particular T cell will find "its" antigen. If a naïve T cell does not bind any of the MHC-peptide complexes it encounters as it browses the surfaces of antigen-presenting cells in the secondary lymphoid tissue, it exits and rejoins the circulation to try again in another tissue. If a naïve T cell does encounter an APC expressing an MHC-peptide complex to which it binds with high affinity, it stops migrating and initiates an activation program that produces a diverse array of cells that orchestrate the short-term and long-term responses to infection. Several signals are needed to activate T cells. SO naive t cells circulate through the blood and enter secondary lymph organs like lymph nodes. Here it takes them 12 to 24 hours to sample all of the antigens present in that area. If they do NOT encounter an antigen to which they are specific for they reenter they blood to circulate to another lymph node to restart the process. IF they DO encounter an antigen to which they are specific for the T cell can bind and become activated. There are several signals involved in activation and the process is explained by the two signal hypothesis (but keep in mind it really requires 3 sets of signals for activation.
NOW MOVING ON TO SIGNAL 2. What is T-cell anergy?
In 1987, Helen Quill and Ron Schwartz recognized that high-affinity TCR-MHC interactions in the absence of functional APCs led to T-cell nonresponsiveness rather than activation: a phenomenon they called T-cell anergy. They advanced the simple, but powerful two-signal hypothesis. We now know that there are costimulatory and coinhibitory receptors: T cell anergy is basically t cell nonresponsivness
What is the two signal hypothesis? what occurs during each signal?
Even though it is often still referred to as the two-signal hypothesis, full T-cell activation actually requires three sets of signals: •Signal 1 = antigen-specific TCR engagement •Signal 2 = contact with costimulatory ligands •Signal 3 = cytokines directing T-cell differentiation into distinct effector cell types (helper vs. cytotoxic T cells) SIGNAL 1 is T Cell receptor signaling. The T Cell receptor is binding to the complex formed by the MHC class II molecule and the peptide, triggering a singling process (signal I) SIGNAL 2 is a costimulatory interaction. The T Cell is also interacting with the APC through a different set of receptors (CD28, CD 80) which trigger a second signal. What is interesting is not all cells express these costimulatory receptors which, in turn, leads to differences in how that T Cell behaves. SIGNAL 3 is cytokine signaling. Cytokine signaling can be paracrine stimulation - so for ex. the APC is secreting IL-12 which binds to a receptor on the T cell activating JAK/SAK signaling - OR autocrine signaling - so basically in response to that activation the T cell can express IL-2 which can bind to the IL-2 receptors on itself We will see later that IL-2 is a strong promoter of cell proliferation
What 2 events can induce anergy?
Experiments with cultured cells show that if a naïve T cell's TCR is engaged (Signal 1) in the absence of a suitable costimulatory signal (Signal 2), that specific T cell clone becomes unresponsive to subsequent stimulation, a state referred to as clonal anergy. There is good evidence that both CD4+ and CD8+T cells can be anergized, but most studies of anergy have been conducted with CD4+ TH cells. The requirement for costimulatory ligands to activate a T cell decreases the probability that autoreactive T cells that have escaped the thymus will be activated and become dangerous. Interactions between coinhibitory receptors and ligands can also induce anergy. This phenomenon, which applies only to activated T cells that have up-regulated coinhibitory receptors, could help curb T-cell proliferation when antigen is cleared. Such cells can become TREGS. SO you can have (1) binding on the MHC and TCP to have signal 1 but without the constimlaory receptor you get anergy. (so the cell is activated but non responsive) and (2) the cohibitory signal can also play into anergy and nonresponsiveness
We keep saying that these T cell subsets are "HELPER" cells BUT how do they help? Provide an example of TFH and TH1 cells.
It is interesting to look at two examples to understand how helper T cells can provide help in the immune response TFH cells interact directly with B cells and generate effector cytokines, such as IL-21 and IL-4, which induce B-cell proliferation and differentiation into antibody-producing plasma cells. SO in order to get a plasma cell you must first have the activation of the TFH cell this helps with the control of the activation (so it ensures we do not have wrongfully activated plasma cells) TH1 cells provide indirect help to CD8+ T cells by interacting with antigen-presenting cells and producing effector cytokines, such as IFN-γ, that license the antigen-presenting cell to finalize CD8+ T-cell differentiation into cytotoxic T cells. TH1 cells also produce IL-2, which enhances CD8+ T-cell proliferation.
Are helper T cells "stuck" in their lineage?
NO Investigations now suggest that the relationship among TH-cell subpopulations may be more plastic than previously suspected. At early stages in differentiation, at least, helper cells may be able to shift their commitment and produce another subset's signature cytokine(s). In other words, the adoption of a helper T-cell lineage is not always a lifelong commitment. In fact, multiple helper T-cell subsets, including TH17 and pTREG lineages, have the ability to differentiate into other helper subsets. In contrast, TH1 and TH2 lineages may be more stable.
what are negative costimulatory receptors and what do they do?
Negative costimulatory receptors help turn activation off: CTLA-4, PD-1, and BTLA CTLA-4 (CD152) Induced within 24 hours after activation, peaks 2-3 days post-stimulation Binds to B7-1/B7-2 with higher affinity than CD28 but shuts down signaling pathways ("putting the brakes on") PD-1 (program death-1, CD279) and BTLA (B- and T-lymphocyte attenuator) PD-1 may help to mediate T-cell tolerance in nonlymphoid tissues BTLA may downregulate inflammatory and autoimmune responses There are also three cohibit receptors. CTLA-4, PD-1, and BTLA. CTLA-4 is actually induced after activation and competes with CD28 binding. This can eventually lead to the inactivation of that T cell. So after a few days of activation the t cell starts expressing CTLA-4 receptors to prevent its activation ( this is a way to limit the immune response in time) and prevent to much of an immune response. PD-1 helps mediate T cell tolerance in non lymphoid tissues. so it have similar roles in stoping activation but its t cell tolerance.
One to two days after successful engagement with a dendritic cell in the T-cell zone of a secondary lymphoid organ, a naïve T cell........
One to two days after successful engagement with a dendritic cell in the T-cell zone of a secondary lymphoid organ, a naïve T cell enlarges into a blast cell and undergoes repeated rounds of cell division. Signals 1 plus 2 induce up-regulation of expression and activity of prosurvival genes (e.g., Bcl-2), as well as the transcription of genes for both IL-2 and the α chain (CD25) of the high-affinity IL-2 receptor. The combined effect on a naïve T cell results in robust proliferation. Activated T cells divide two or three times per day for 4 to 5 days, generating a clone of progeny cells. Activated T cells and their progeny gain unique functional abilities, becoming memory and effector helper or cytotoxic T cells. Whereas naïve T cells can live for months, effector cells tend to be short-lived and have life spans that range from a few days to a few weeks. Memory cells typically live longer, and some extend their lives by dividing over the many months or even years that they are present in an organism.
What is the result of t cell activation?
PLCγ signaling and activation of the transcription factors NF-κB and NFAT PLCγ binds LAT in proximity to membrane phospholipids PLCγ catalyzes the splitting of PIP2 to soluble IP3 and membrane-DAG IP3 induces calcium release Calcium binds calcineurin which in turn dephosphorylates NFAT NFAT enters nucleus DAG activates PKC which leads to translocation of NF-κB to nucleus SO basically we have activation of Lck which drives the pros. of a number of proteins which activate two different pathways.(1) pathway that is activated is a pathway that depends on PLCγ and the other (2) is a pathway that depends on Ras-ERK MAIN IDEA: Following tyrosine phos. by Lck we have lipid signaling which triggers the transcription factors NF-κβ and NFAT to be transcribed and translocated into the nucleus. There is also a third TF that gets transcribed called AP-1
What are positive costimulatory receptors? what do they facilitate? what are two ex?
Positive costimulatory receptors facilitate activation: CD28 and ICOS CD28: Generally involved in initial activation events in T cells 44 kDa glycoprotein homodimer expressed on majority of T cells Markedly enhances TCR-induced proliferation and survival Binds to B7-1 and B7-2 expressed by APCs ICOS: Expressed on memory and effector T cells Inducible costimulator, binds ICOS-ligand on activated APCs May help to maintain activity of already differentiated cells There are basically costimulatory and coinhibitory receptors. Costim are there to drive the immune response while coinhib are there to stop and prevent to strong of of an immune response (such as to many t cells from being activated). There are two costim receptors CD28 and ICOS. CD28 is involved in activation of naive t cells. ICOS comes in after activation and helps maintain the cell
What transcription factor is transcribed upon activation of Ras-ERK signaling?
Ras-ERK signaling and activation of transcription factor AP-1 Ras pathway triggers MAP Kinase (MAPK) activation MAPK cascade phosphorylates in sequence RAF, MEK, and ERK ERK activates transcription factor AP-1 AP-1 also gets translocated into the nucleus. AP-1 depends on the MAP Kinase Cascade. MAIN IDEA: once you have T Cell receptor engagement by a MHC molecule you get clustering and activation of Lck and phos. of CD3 (so tyrosine phos). This triggers a chain of events that involves lipid signaling which is the end result in the translocation of AP-1, NFAT, and NF-κβ into the nucleus. This activates genes that regulate survival, proliferation and effector functions.
What are the functions of T follicular helper (TFH) cells?
T follicular helper (TFH) cells are now firmly established as a distinct helper T-cell subset. Whereas TH2 cells focus their help on the response to worms and enhance IgE production, TFH cells provide cognate help to a wide range of B cells and enhance switching to a variety of antibody classes. TFH cells are required for the formation of germinal centers and provide the signals that drive affinity maturation of B cells. To help in these functions, they express: •CD40L required for cognate B-cell help •CXCR5 that attracts them to B-cell follicle These cells help B cells diff. into plasma cell and also help with the production of antibodies.
How does T cell activation begin? what follows activation?
T-cell activation begins with tyrosine kinase Lck: CD4 and CD8 cytoplasmic tails guide Lck to TCR-MHC complex Lck phosphorylates ITAMs on CD3 Phosphorylated ITAMs become docking sites for ZAP-70 ZAP-70 phosphorylated by Lck Lck is a kinase that is attached to the membrane of the T Cell but does not have a transmembrane region (its membrane bound but facing the cytoplasm) Lck phos. the tyrosine motifs found in CD3 (once you get aggeration of those molecules from MHC binding). These phos. ITAM motifes then become docking sites for a molecule called ZAP-70. Once ZAP 70 is brought over it is also phos. my Lck. MAIN IDEA: Lck is initiation the signal cascade.
How does memory work?
T-cell activation results in a proliferative burst, effector cell generation, and then a dramatic contraction of cell number. At least 90% of effector cells die by apoptosis after pathogen is cleared, leaving behind an all-important population of antigen-specific memory T cells. Memory T cells are generally longer-lived than effector cells, and are quiescent. Here are some interesting numbers: memory T cells represent about 35% of circulating T cells in a healthy young adult, rising to 60% in individuals over 70 years old. Memory cells respond with heightened reactivity to a subsequent challenge with the same antigen. This secondary immune response is both faster and more robust, and hence more effective than a primary response. SO a naive t cell is activated by an APC --> signal 1 cell receptor binds to MHC complex --> signal 2 --> constimulation with CD28 CD80/86 --> signal 3 IL-2 release. The cell now enters the cell cycle and diff into a stem cell memory cell which is SELF RENEWAL (it can divide and diff). We then get CM T cells which divide into EM T cells which divide into TD cells. These TD cells are fairly quick living and the can not divide anymore (but when they die they leave behind memory t cells)
T or F: Just as TH1 and TH2 cells reciprocally regulate each other, TREG and TH17 cells also cross-regulate each other.
TRUE TGF-β plays a role in the differentiation of both TREG and TH17 cells. Alone, it induces a program that leads cells to the TREGfate. When accompanied by IL-6, however, TGF-β induces TH17 differentiation. How is this possible? TGF-β appears to up-regulate expression of both master regulators FoxP3 and RORγt, which control TREG and TH17 differentiation, respectively. In combination with signals generated by IL-6, TGF-β actually inhibits FoxP3 expression, letting RORγt dominate and induce TH17 development. In barrier tissues where these cells are over-represented, a normal state could favor development of suppressive iTREG population to keep inflammation down. Inflammation from an infection (leading to IL-6 production) would stimulate more antibacterial TH17 differentiation. IF TGF-β is involved in both cells diff. how do we get one or the other? it involves the integration of cytokine signals to drive to a particular subset.
T or F: Helper T-cell subsets often "cross-regulate" each other.
TRUE The cytokines they secrete typically enhance their own differentiation and expansion, while inhibiting commitment to other helper T-cell lineages. This is particularly true of the TH1 and TH2 subset pair, as shown here. Cytokines can achieve TH1/TH2 helper subset cross-regulation •IFN-γ from TH1 responses inhibits IgG1/IgE class switching (a common TH2-induced response) •IL-4 from TH2 responses inhibits production of IgG2a (a common TH1-induced response) •IL-10 from TH2 responses also inhibits TH1 responses by suppressing the production of inflammatory mediators from APCs Master regulators commit T cells to one subset or the other •T-Bet suppresses TH2 pathway gene expression •GATA3 suppresses TH1 pathway gene expression Whats interesting is that the polarizing cytokine does not just drive diff of the cell towards a particular helper subset, BUT ALSO prevents the diff. of that cell into another helper subset. THIS IS CROSS REGULATION.
what is the function of the TH1 and TH2 subsets?
The key polarizing cytokines that induce differentiation of naïve T cells into TH1 cells are IL-12, IL-18, and IFN-γ. These polarizing cytokines trigger signaling pathways in naïve T cells that up-regulate expression of the master gene regulator T-Bet. In turn, this master transcription factor induces expression of signature type 1 effector cytokines, including IFN-γ and TNF, and differentiation of CD4+ T cells to the TH1 lineage. IFN-γ is a particularly potent type 1 effector cytokine. It activates macrophages, stimulating these cells to increase microbicidal activity, up-regulate the level of MHC class II molecules. IFN-γ secretion also induces antibody class switching in B cells to IgG classes TH1 leads to the release of cytokines that induce inflammation The key polarizing cytokine that induces differentiation of naïve T cells into TH2 cells are IL-4. The type 2 effector cytokines produced by TH2 cells help clear extracellular parasitic infections, including those caused by worms. IL-4, the defining TH2 effector cytokine, acts on both B cells and eosinophils. It induces eosinophil differentiation, activation, and migration and promotes B-cell activation and class switching to IgE. These effects act synergistically because eosinophils express IgE receptors (FcεR) that, when cross-linked, release inflammatory mediators that are particularly good at attacking roundworms. Listen the lecture march 30th 16 min IL-4 is the most important cytokine when it comes to differentiation into a TH2 cell
The outcome of T-cell activation is critically shaped by the? what is signal 3?
The outcome of T-cell activation is critically shaped by the activity of soluble cytokines produced by both APCs and T cells. These assisting cytokines are referred to, by some, as Signal 3. Cytokines bind surface cytokine receptors, stimulating a cascade of intracellular signals that enhance both proliferation and/or survival. Interleukin-2 is one of the best-known cytokines involved in T-cell activation and plays a key role in inducing optimal T-cell proliferation, particularly when antigen and/or costimulatory ligands are limiting. TCR and costimulatory signals induce transcription of genes for both IL-2 and the α chain (CD25) of the high-affinity IL-2 receptor. These signals together also enhance the stability of IL-2 mRNA. The combined increase in IL-2 transcription and improved IL-2 mRNA stability results in a 100-fold increase in IL-2 production by the activated T cell. Secretion of IL-2 and its subsequent binding to the high-affinity IL-2 receptor induces activated naïve T cells to proliferate vigorously. As we will see, this is a case of autocrine signaling.
what are the functions of to T helper type 17 (TH17) cells.
These cells are activated by the polarizing cytokines IL-1β, IL-6, IL-23, and TGF-β. The master regulator RORγt, an orphan steroid receptor, becomes active and differentiates activating T cells into this subset These cells are associated with fighting fungal and extracellular bacterial infections and produce the cytokines IL-17A, IL-17F, IL-21, and IL-22. However, the issue is that production of IL-17A is associated with chronic inflammatory and autoimmune responses. TH17 cells are involved in extreme inflammation and have also been linked to autoimmune disorders what important here is that these are cells that are activated by IL-Iβ which is involved with proinflmasomes.
What are the functions of are peripheral TREG (pTREG)?
These cells are similar in function to the TREG cells that are generated in the thymus: they suppress immune responses. These cells arise from naïve T cells that are activated in secondary lymphoid tissue in the presence of TGF-β. TGF-β induces FoxP3 master regulator, shifting activating cells into this subset. iTREG cells secrete IL-10 and TGF-β to downregulate inflammation (by inhibiting APCs) and suppress other T-cell subsets. so these cells are involved with impairing the immune response. Also these are the T cells that had high affinity BUT NOT TO HIGH affinity. TGF-β is a cytokine that helps polarize t cells into the TH17 subset but also the TREG subset. SO TGF-β helps diff. into two different subsets, one of them being extremely inflammatory and the other suppressing the immune response.
what are TRM cells?
They are permanent residents of previously infected tissue •Respond upon reinfection •CD8+ TRM found in multiple tissues These cells reside at the site of infection to be activated as soon as they are needed. These cell are a little more experienced considering they are waiting for the exposure of a particular pathogen at a particular site.
T or F: Memory cells appear to have less stringent requirements for activation than naïve T cells.
True For example, naïve T cells are activated almost exclusively by dendritic cells, whereas memory T cells can be activated by macrophages, dendritic cells, and B cells. Memory cells express different patterns of surface adhesion molecules and costimulatory receptors that allow them to interact effectively with a broader spectrum of APCs. They also appear to be more sensitive to stimulation and respond more quickly. This may, in part, be due to epigenetic changes that enhanced access to genes required for activation. There is a large number of different cells that can activate memory cells which allows for a greater chance of encounter and hence activation --> response. So the secondary reaction is more robust
What are superantigens?
We will finish by mentioning superantigens, a special class of T cell activators. These viral or bacterial proteins bind simultaneously to specific Vβ regions of T-cell receptors and to the α chain of MHC class II molecules. This clamp-like connection mimics a strong TCR-MHC interaction and induces activation, bypassing the need for TCR antigen specificity. In other words, this interaction effectively "short circuits" the need for costimulation. The large-scale T-cell activation leads to inflammation that can cause disease, such as toxic shock syndrome. Superantigens are molecules that help stabilize the interaction between MHC molecules and the T cell. They stabilize this interaction so well that you can have activation of the T cell in the absence of signal 2. (This can lead to over activation of the t cell and toxic shock) This is an advantage for the pathogen bc it helps them to survive by distracting our body by making it focus on something else
How can we differentiate between memory T cells, Naive T cells, and effector T cells?
by their surface protein expression Naïve, effector, and memory T cells display broad differences in surface protein expression. Three surface markers can differentiate the sets: CD44 - increases in response to TCR-mediated activation signals CD62L - adhesion protein that regulates homing to secondary lymphoid organs CCR7 - chemokine receptor that regulates homing to secondary lymphoid organs CD69 - C-type lectin that prevents immune cells from leaving tissue
what are TEM cells - effector memory T cells?
•Travel to/between tertiary tissues •Contribute better to first-line defenses •Shift right back into effector functions on second antigen exposure tertiary tissues are the site of infection
The CD4+ cell population is heterogeneous and made of distinct helper subtypes that make distinct sets of cytokines. This population coordinates, broadly speaking, two types of responses called type 1 and type 2 responses. what are type 1 and type 2 responses?
•Type 1 responses are triggered by viral and many bacterial infections and polarize CD4+T cells to the TH1 and TH17 helper subsets. These work with other immune cells (including ILC1s and ILC3s) to generate protective cytotoxic responses. •Type 2 are triggered by larger parasites, including worms, protozoa, and allergens. These polarize CD4+ T cells to TH2 and TH9 helper subsets, which work with other populations of immune cells (including ILC2s) to generate an IgE response. Using these helper subsets, an organism can "tailor" a response to a particular type of pathogen. Type 1 deal with intracellular pathogens, bacteria, and viruses. Type 2 deal with extracellular pathogens (ex. worms) the cytokine provided by the APC that drives the t cell towards a particular subset, the different master gene regulators, and the different effector cytokines ALL ADD TO THE DIVERSITY
