Immunolgy Test 3

What can be delivered to a rhesus negative mother during pregnancy to prevent the generation of a primary immune response against rhesus positive fetal red blood cells? How does the drug prevent the primary immune response?

A controlled concentration of IgG antibodies specific for the rhesus antigen on red blood cells can be given to a rhesus negative mother during the final trimester (and again after birth) to prevent the mother from generating a primary response against the fetal red blood cells. The IgG antibodies cross the placenta and bind to the fetal red blood cells (but the concentration of antibody is not high enough to cause fetal health problems). If there is mixing of maternal and fetal blood, the maternal naïve B-cells will not be activated because the inhibitory Fcγ receptor will be engaged by the IgG antibodies that are attached to the fetal red blood cells.

What is a memory response, also called a secondary immune response? Compare a memory/secondary immune response to a primary immune response regarding the speed of the response and the strength of the response

A memory/secondary immune response is the adaptive immune response produced upon second d and subsequent encounters with an antigen. The memory/secondary immune response is activated faster and is more effective than the primary immune response.

What is a naïve B-cell? What type of cell do naïve B-cells turn into following activation?

A naive B-cell is one that has not yet been activated by antigen. Following activation, a naïve B-cell differentiates into a plasma cell that secretes antibody (or as we will learn later, some naïve B-cells can instead differentiate into a memory B-cell, which functions during a memory response).

What is a naïve T cell? What is an effector T cell?

A naïve T cell is one that has not yet encountered its antigen. An effector T cell is one that has been activated by its antigen and now has effector function.

What is a plasma cell? What properties distinguish a plasma cell from a naïve B-cell?

A plasma cell is a terminally differentiated B cell that secretes antibody. Plasma cells no longer express the B cell receptor on the surface, and they do not express MHC class II molecules because they have already been activated (and therefore do not need to display the B-cell receptor or interact with T cells). They are terminally differentiated, so they do not have the capability of any further proliferation, affinity maturation or class switching.

What is an Fc receptor?

A receptor that binds the Fc portion (heavy chain constant region) of an antibody.

What primary symptoms would you expect in patients that do not produce functional B cells, or only produce low affinity IgM antibodies (hyper IgM syndromes)?

Although antibodies are also involved in combating intracellular infections (i.e., antibodies are required for ADCC and they can recognize viruses during the extracellular phase), individuals still have other defenses for combating intracellular infections,(cytotoxic T cells, NK cells) although the infections may not be dealt with as quickly and efficiently in the absence of antibodies

What is the immune system producing an inflammatory immune response against in Crohn's disease?

An inflammatory immune response is produced against commensal microbes.

What is the immune system producing an inflammatory immune response against in Celiac disease

An inflammatory immune response is produced against gluten. Gluten is a nonmicrobial environmental antigen, so the response is supposed to be production of Tregs and oral tolerance.

What kind of immune response is generated in response to c) microbial antigens that have breached the epithelial barrier (includes opportunistic commensals and pathogens) (i.e., what type of immune cells and molecules are produced)?

An inflammatory response is generated to clear an infection caused by any microbe that breaches the epithelial barrier, just like in the systemic immune system. If there is a breach in the barrier, epithelial cells will secrete inflammatory cytokines rather than anti-inflammatory cytokines, which allows an inflammatory immune response to be produced- the balance tips away from Tregs and towards the other T-cell subsets (e.g., TH17 and TH1 cells) and other immune cells (e.g., neutrophils) can be recruited to the site of infection. As immune responses are proactively produced against antigens in the lumen of the gut, there may already be an adaptive immune response ready and waiting in the underlying tissue to deal with the infection quickly with minimal inflammation

What signal determines the antibody class that will be produced during class switching, and what provides the signal?

Class switching is largely determined by the cytokinesreceived by the B-cell. TFH cells can deliver the cytokines that influence class switching, but other CD4 T-cellsubsets can also provide cytokines that influence class switching

What kind of immune response is generated in response to b) commensal microbes that have not breached the epithelial barrier (i.e., what type of immune cells and molecules are produced?

Commensal antigens (actively brought into the mucosal tissues by M-cells or other routes such as dendritic cells sampling the lumen) will be able to activate dendritic cells through PAMPs. However, in the absence of an infection, dendritic cells are maintained in a tolorogenic state due to the anti-inflammatory microenvironment inside the mucosal tissue (see Q9). The dendritic cells activate Tregs against the antigens. Other effector T cell subsets are also produced, and travel to the lamina propria, ready for a breach in the epithelial layer, but the Tregs keep the inflammatory T-cell subsets in check in the absence of infection. Plasma cells secreting IgA (following initial secretion of IgM as in the systemic immune system) are also produced- the IgA antibodies are transported across the epithelium and neutralize commensal microbes keeping the microbial load in check.

What type of effector cell do naïve CD8 T cells turn into, and what is the function of the effector cell?

Cytotoxic T cells, which function to destroy infected host cells.

How can immature dendritic cells become activated? (There are 2 ways).

Dendritic cells have many different pattern recognition receptors (PRRs). They become activated when a pathogen associated molecular pattern (PAMP) activates a PRR. Dendritic cells can also become activated by pro-inflammatory cytokines that are produced during an infection even if the dendritic cell has not been activated by one of its PRRs.

What antibody classes protect the mucosal surfaces and what function do the antibodies perform at the mucosal surface?

Dimeric IgA is the primary antibody class that protects mucosal surfaces. IgM also contributes to protection at mucosal surfaces, but IgM is present at a lower concentration and it is a lower affinity antibody. IgA and IgM perform the sole function of neutralization at mucosal surfaces, which does not produce inflammation or tissue damage. We do not get opsonization or activation of the complement system (other functions performed by monomeric IgA in the systemic immune system) at mucosal surfaces because other immune cells and complement proteins are not present at mucosal surfaces.

What are follicular dendritic cells (FDCs): Where are they found and what role do they play? In what form do they present antigen to B cells?

Follicular dendritic cells are found in the B-cell areas in secondary lymphoid tissues They are not blood cells and are not derived from hematopoietic stem cells in the bone marrow. They are not phagocytic, so they do not internalize antigen. They display intact antigen to Bcells because we need to activate B-cells that will produce antibodies against antigens that are accessible on the surface of pathogens.

What is a primary focus? Where is it located, and what is the primary antibody class secreted from plasma cells in a primary focus?

Following activation, B cells and conjugate TFH cells move to the medullary cords and form a primary focus, which is a focus of B cells and conjugate T cells undergoing proliferation. Some B cells in the primary focus differentiate to plasma cells that secrete low affinity IgM antibody.

What is a germinal center? Where is it located, and what two events take place in the germinal center?

Following initial proliferation in the primary focus, most B cells and conjugate TFH cells move back to the lymphoid follicles (B-cell area) to form a germinal center. The gene encoding the AID enzyme is activated in the germinal center, so somatic hypermutation (resulting in affinity maturation) and class switching occur in the germinal center to produce high affinity, class switched antibodies.

Which 3 signals promote B-cell activation in response to a thymus-dependent antigen?

I. Binding of antigen to B-cell receptor. II. Binding of complement fragment C3d to the B-cell co-receptor. III. Signals delivered by conjugate T follicular helper cell (TFH): 1) Binding of CD40 ligand on the T-cell to the B-cell CD40 receptor, 2) binding of cytokines secreted by the TFH cell to Bcell cytokine receptors. The signals from TFH cells are required for naïve B-cell activation and proliferation, and, also for somatic hypermutation and class switching.

If a T-cell recognizes the peptide:MHC complex presented by a dendritic cell then it becomes activated. What 3 signals are needed for T cell activation?

I. T-cell receptor recognizes the peptide:MHC complex presented by the dendritic cell. II. The B7 co-stimulatory signal provided by the dendritic cell. B7 binds to the CD28 receptor on the T cell. III. Cytokines ▪ The cytokine IL-2 is required for T-cell proliferation following activation. The Tcell itself is the source of the IL-2. After the T cell receives the first 2 signals, it starts to produce IL-2 and a high affinity IL-2 receptor. ▪ Cytokines will also determine which effector subset a naïve CD4 T cell will differentiate into during activation.

How does the B-cell requirement of T-cell help protect the body from self-reactive B-cells that escaped negative selection (i.e., B-cells with a receptor that recognizes self-antigen)?

If a B cell receptor binds to a self-antigen it will not likely be activated because there will not likely be a TFH cell that recognizes the same antigen (T-cells that recognize self-antigen become anergic in the absence of co-stimulation from dendritic cells). B-cells undergo apoptosis if they bind antigen, but do not encounter a conjugate T cell.

d. What is a granuloma and why does it form?

If activated macrophages can't clear an infection then they form a granuloma, which is a collection of macrophages and TH1 cells that attempt to wall off the pathogen and prevent pathogen dissemination.

What is the most abundant antibody class in the body

IgA due to the large amount of IgA that is produced to protect mucosal surfaces

What are the 5 antibody classes?

IgA, IgG, IgM, IgD, IgE

Which antibody class protects against parasite infections? Which effector cells does the antibody interact with?

IgE. Mast cells, basophils and eosinophils have receptors for binding IgE. We will discuss IgE mediated responses to parasites and allergens a lot more in the fourth part of the course

What is the most abundant antibody class in blood serum

IgG. It is a good 'all round' antibody class able to perform various functions (see table in handout).

Which antibody classes are most effective at activating the classical complement pathway?

IgM and IgG Monomeric IgA can activate the classical complement pathway, but most IgA is dimeric IgA found at mucosal surfaces where complement proteins are not found. The primary function of IgA is neutralization

Why are young infants vulnerable to infections in the first year?

IgM levels gradually rise during the first year, but it takes time to develop high levels. IgG that came from the mother steadily declines after birth: an infant starts to produce appreciable levels of its own IgG at approximately 3 months, but levels are relatively low until ~1 year of age. Levels of IgA also start to steadily rise from about 3 months but are relatively low until ~ 1 year if age. However, an infant can be supplied with maternal IgA from breast milk until its levels are high.

Regarding the need for TFH cell help, what is the difference between a thymus dependent antigen response and a thymus independent antigen response? What is the primary antibody class produced during a thymus-independent response?

In a thymus dependent antigen response, the B-cellrequires T-cell help to become activated and then to undergo somatic hypermutation and class switching in the germinal center. In a thymus independent antigen response, a B-cell can be activated in the absence of T-cell help. The primary antibody class secreted is low affinity IgM, as it occurs outside of the germinal center

Where do B-2 cells meet their antigens?

In the B-cell areas in secondary lymphoid tissues. In the lymph nodes, the B-cell areas are called the lymphoid follicles.

How is it that such proactive immune responses do not result in chronic inflammation of mucosal tissues?

In the absence of a proactive immune response, frequent infections would result in chronic inflammation of mucosal tissue because the surfaces would be frequently breached. Inflammation also damages host tissues, so chronic inflammation would compromise the function of the mucosal surfaces (e.g. absorption of food in the small intestine).

How do the epithelial cells participate in the immune responses that are generated against microbial antigens?

In the absence of infection, epithelial cells secrete anti-inflammatory cytokines, which help promote the anti-inflammatory environment of mucosal tissue and the anti-inflammatory proactive response to commensals. Epithelial cells have PRRs at the cell surface and in the cytosol that can detect pathogens that make it across the mucus layer to the epithelial surface, or into the epithelial cell. Activation of the PRRs by PAMPs causes epithelial cells to secrete inflammatory cytokines that promote an inflammatory immune response by tipping the balance away from Tregs and towards inflammatory T-cell subsets. As proactive immune responses have already been generated, hopefully the immune response will deal with the infection promptly.

How are antigens brought from a site of infection to a lymph node?

In the lymphatics. Extracellular fluid surrounding tissues forms lymph, which is drained by the lymphatics to the secondary lymphoid tissues. Dendritic cells circulate in tissues. Following activation by an antigen, they travel in the lymphatics to take the antigen to a draining secondary lymphoid tissue. Free antigen (i.e., that has not been taken up by a cell) will also enter the lymphatics and be transported to secondary lymphoid tissues where it can be taken up by dendritic cells resident in the secondary lymphoid tissue. If antigens are in the blood, then they will be transported in the blood to the spleen, which filters blood borne antigens

What kind of immune response is generated in response to a) harmless food antigens (i.e., what type of immune cells and molecules are produced?),

In the mucosal immune system, dendritic cells (or perhaps a specific subset of dendritic cell) constantly take up antigen and traffic to secondary lymphoid tissues, even if they are not activated by PAMPs. Harmless food antigens are not going to activate dendritic cells through PAMPs, so a dendritic cell presenting harmless food antigens will travel to the mesenteric lymph nodes and secrete anti-inflammatory cytokines to activate antiinflammatory Tregs, which results in tolerance to the antigen. We do not get the activation of inflammatory T-cell subsets or B-cells. Oral tolerance refers to the phenomenon that mucosal immune system and systemic immune system tolerance (unresponsiveness) are developed in response to non-pathogen peptide antigens taken in by the oral route.

What is antibody dependent cell mediated cytotoxicity (ADCC)? Which antibody class mediates ADCC, and which effector cell is involved?

Infected host cells display pathogen antigens on the surface on MHC class I. IgG antibodies (that were generated against antigens when the pathogen was outside the cell) bind to their antigen when presented on the host cell surface. Natural killer cells have an Fcγ receptor that binds to the IgG at the host cell surface. Binding to IgG through its Fc receptor causes the natural killer cell to destroy the infected host cell. ADCC complements the function of cytotoxic T cells during the adaptive immune response.

How do cytotoxic T-cells recognize their target cell? What is a cognate pair, and why do CD8 T cells form a cognate pair with their target cell?

Infected target cells will display pathogen-derived peptides on MHC class I molecules on the cell surface. If the cytotoxic T-cell recognizes its specific peptide:MHC complex (i.e., the same complex that activated the T-cell) on the target cell, then it will kill the target cell. Once activated, a T-cell does not need a co-stimulatory signal, it only need recognize the peptide:MHC complex.

What is neutralization? Which antibody classes are effective at neutralization and why?

It involves the binding of antibodies to surface structures that are used by an organism or toxin to enter a cell. Therefore, neutralization prevents attachment to host cells. IgG and IgA are effective neutralizing classes because they are high affinity antibodies that have undergone affinity maturation. IgG is the primary neutralizing antibody class in systemic tissues, and IgA is the primary neutralizing antibody class at mucosal surfaces. If antigens are present at low concentration, we must have high affinity antibodies. IgM can also function in neutralization, but it is a lower affinity antibody, and it does not move into tissues as easily due to its size, so it is less effective

What is anergy (i.e., to become anergic)?

It means the T-cell becomes permanently unresponsive, so if the T-cell encounters its antigen again in the future it will be unresponsive to it and will not become activated. Anergic cells do not last long in circulation.

Which 3 things happen when an immature dendritic cell becomes activated to turn into a mature dendritic cell?

It up-regulates the co-stimulatory molecule B7, which is required for T cell activation (binds to CD28). It up-regulates the presentation of antigens on MHC molecules. It up-regulates a chemokine receptor (CCR7), which directs the dendritic cell towards a chemokine produced in secondary lymphoid tissues

Where are M cells located, and what is their function?

M cells (microfold cells) are in the epithelium directly overlying the Peyer's patches and isolated lymphoid follicles. The cells transport antigens from the gut lumen into the underlying secondary lymphoid tissues where the antigen is taken up by dendritic cells, which initiate activation of adaptive immune responses.

b. Why aren't macrophages constantly maintained in an activated state?

Macrophages produce potent antimicrobial substances to destroy the contents of endosomes/phagosomes, and the antimicrobial substances can also damage host bystander cells. Macrophages increase production of potent antimicrobial substances following activation. Therefore, macrophages are kept at ground state in the absence of an infection to limit unnecessary production of antimicrobial substances that can also harm host cells. Additionally, it takes more energy for the macrophage to be maintained in an activated state, so we do not want to waste cellular energy unnecessarily.

What are memory B cells and how do they differ from naïve B cells?

Memory B cells are long lived B cells that differentiated from activated B cells during the primary immune response. Memory B cells underwent class switching and affinity maturation during the primary immune response, so they display high affinity, class switched receptors.

What are the two broad classes of memory T cells, and how do they differ from naïve Tcells?

Memory T cells differentiated from activated T cells during the primary immune response. There are two broad classes of memory T cells: 1) Effector memory T cells are long-lived effector T cells that circulate in peripheral tissues and can respond rapidly when they encounter their antigen in tissues. They are already differentiated to a particular T-cell subtype, so they can respond immediately. 2) Central memory T cells are more like naïve T cells in that they circulate in the secondary lymphoid tissues and retain the potential for proliferation and differentiation to produce effector T cells. However, antigen-specific central memory T cells will be present in greater numbers compared to the antigen-specific naïve T cells that were present before primary infection. They are also activated more readily than naïve T cells (and will therefore differentiate into effector T-cell earlier in the course of an infection).

Where are mucosal surfaces located?

Mucosal surfaces line the body's glands and internal tubular structures: respiratory tract, gastrointestinal tract and urogenital tract

Why must mucosal tissues be proactive in generating immune responses against microbial antigens at mucosal surfaces?

Mucosal tissues are thin and permeable and more vulnerable to being breached by pathogens and the commensal microbes that colonize mucosal surfaces

What is mucus?

Mucus is a secretion that contains a high proportion of glycoproteins called mucins. It is secreted by goblet cells in the epithelial layer of the mucosal surface.

What cells produce mucus and how does it protect mucosal surfaces?

Mucus lubricates and protects mucosal surfaces: it physically impedes microbes from reaching the epithelial later, it serves to tether antibodies and antimicrobial substances in place at the mucosal surface, and it turns over (i.e., is replaced) every couple of days.

What is the difference between natural and induced T regs?

Natural Tregs are produced in the thymus during T cell development; some cells that bind too strongly during negative selection become Tregs instead of undergoing apoptosis. Induced Tregs differentiate from naïve CD4 T cells following activation in a secondary lymphoid tissue in the presence of anti-inflammatory cytokines. Induced Tregs are primarily produced in the mucosal immune system (which we will discuss in chapter 10) is response to harmless antigens like commensal microbes and food antigens

How are naïve B cells inhibited by IgG antibodies that were produced during a primary immune response? How can this inhibition of naïve B cells be beneficial to the host during a secondary immune response? When might this inhibition of naïve B cells be detrimental to the host during a secondary immune response (think about when we have a pathogen such as Influenza virus that can mutate rapidly)?

Naïve B cells have an inhibitory Fcγ receptor (a receptor that binds IgG), which prevents activation of naïve B-cells when IgG antibody binds to it. During a primary response, there is no antigen-specific IgG antibody in circulation, so the inhibitory Fcγ receptor is not engaged. During a memory/secondary response, the antigen will be bound by the long-lived IgG that remains in circulation after the primary response. Therefore, during a memory/secondary response, a naïve B-cell that binds antigen with its B-cell receptor will simultaneously bind the IgG coating the antigen with its Fcγ receptor, which will inhibit activation of the naïve B cell.

Do non-mucosal tissues generate proactive immune responses?

No. Non-mucosal tissues do not often come into contact with pathogens. Therefore, adaptive immune responses are only generated in response to an infection, and these reactive immune responses are inflammatory in nature. Inflammatory immune responses also cause damage to host tissue, which has to be repaired afterwards, but infections do not happen very often in systemic tissues, so occasional inflammation followed by repair does not compromise the function ofsystemic tissues.

What are the 2 classes of cytotoxins stored in the granules of cytotoxic T cells? What is the purpose of each class of cytotoxin?

Perforin disrupts the target cell membrane. Granzymes are then delivered into the target cell, and they are proteases that activate the caspases that induce apoptosis.

Dendritic cells can take-up antigens specifically (via PRRs binding to PAMPs) or nonspecifically by macropinocytosis (non-specifically engulfs extracellular material and brings it into the cell in an endosome). What normally prevents dendritic cells being activated by selfantigens if they take up self-antigens via macropinocytosis?

Self-antigens do not activate PRRs, and they do not produce inflammation

What are the primary effector cells that respond to opsonized pathogen?

Susceptibility to extracellular infections.

How do macrophages in systemic tissues and mucosal tissues differ with regard to the production of inflammatory cytokines?

Systemic tissue macrophages are phagocytic and they also secrete inflammatory cytokines in response to microbes to generate an inflammatory response. Mucosal tissue macrophages are only phagocytic; they do not secrete inflammatory cytokines in response to microbes.

In which part of the lymph node do T cells sample the antigens presented by dendritic cells?

T cell areas

What T-cell subset functions to provide activating signals to a B-cell during B-cell activation?

TFH cells.

What type of antigens can activate TI-1 and TI-2 B-cell responses, and what is the advantage of having a populations of B-cells that are able to be activated by TI-1 and TI-2 antigens?

TI-2 antigens are highly repetitive polysaccharide (carbohydrate) antigens in bacterial capsules. The highly repetitive structures can cross-link a high number of B-cell receptors and send a strong signal to activate the B-cell without T-cell help. Bacteria with a capsule are more resistant to phagocytosis, so their antigens do not get processed efficiently by dendritic cells for presentation to T-cells. Therefore, T-cell dependent (i.e., thymusdependent) B-cell activation is difficult. It is primarily B-1 cells (and another subset called marginal zone B cells in the spleen) that produce TI-2 antigen responses. TI-1 antigens include common bacterial PAMPs, such as LPS and DNA that may reach high concentration during an infection. At high concentration, they can activate B-cells nonspecifically (i.e., regardless of B-cell receptor specificity) without T-cell help. B-cells are activated by binding of the PAMP to B-cell PRRs. Some of the B-cells that were activated nonspecifically will produce antibodies that recognize antigens on the pathogen. Thymus-dependent B-cell responses are also activated, but the thymus-independent response arises earlier and provides quick initial protection while the body waits for the thymus-dependent response to develop

What is meant by 'linked recognition' regarding the antigen recognized by a B-cell receptor and it's conjugate TFH cell receptor?

The B-cell receptor and the conjugate TFH cell receptor do not recognize the same antigen, but the antigens must be a part of the same overall structure. For example, in the case of a pathogen, a B-cell receptor will be activated by a surface antigen. It will then internalize the whole pathogen and break it down. The proteins will be processed into small peptide fragments and presented on the surface on MHC class II to TFH cells. Therefore, the peptide antigens that are being presented on MHC II to TFH cells are different from the antigen that activated the B-cell receptor, but the antigens are a part of the same pathogen (i.e., they are linked in the same overall structure).

What happens if a T cell recognizes its peptide:MHC complex in the absence of a costimulatory signal? Why does this happen?

The T cell will become anergic. This happens as a protective mechanism to minimize the chances of a T-cell becoming activated by a self-antigen. Self-antigens should not activate dendritic cells to produce the co-stimulatory molecule B7 because self-antigens do not usually contain PAMPs (pathogen associated molecular patterns) and they do not produce inflammation. Therefore, if a dendritic cell is presenting antigen in the absence of a costimulatory molecule, it is likely a self-antigen.

What is opsonization?

The coating of an antigen with a molecule (e.g., antibody and/or complement) that facilitates uptake of the antigen by phagocytes. The phagocytes that ingest opsonized pathogens are macrophages and neutrophils. The IgG class is the most important class that functions in opsonization. Monomeric IgA can also be an opsonizing antibody, but most IgA is dimeric IgA found at mucosal surfaces where there are no macrophages or neutrophils.

Which secondary lymphoid tissues serve the small intestine?

The gut associated lymphoid tissues (GALT) and mesenteric lymph nodes. The GALT of the small intestine include the Peyer's patches and isolated lymphoid follicles, which are located just under the epithelial layer. The Peyer's patches are larger and have characteristic B cell and T cell areas, whilst the isolated lymphoid follicles are smaller and may contain only a single lymphoid follicle (as the name implies). The appendix is located where the small and large intestines meet- it is also classed as a secondary lymphoid tissue although its importance is unclear; it can be removed without apparent consequences.

In a newborn infant, where do the IgM, IgG and IgA antibody classes come from?

The infant produces its own IgM, which begins before birth and steadily rises during the first year. IgG comes from the mother; it is transported across the placenta during fetal development. At birth, an infant has the same IgG antibodies in circulation as the mother. After birth, maternal IgG gradually declines until there is little left by about 6 months at which point the infants's own IgG levels have begun to rise and continue to steadily rise throughout the first several years of life. IgA to protect mucosal surfaces comes from the mother through breastmilk. An infant begins producing its own IgA after birth and levels steadily rise throughout the first several years.

c. What 2 signals does the macrophage need to become upregulated?

The macrophage requires the cytokine IFN-gamma and the CD40 ligand (CD40L), which binds to the CD40 receptor on the surface of the macrophage. The macrophage will present material derived from its vesicles on MHC class II molecules. When an activated TH1 cell recognizes the antigen/MHC complex presented by the macrophage (i.e., if it is the same complex that activated the TH1 cell) then the TH1 cell will form a conjugate pair with the macrophage and deliver the 2 signals.

Upon activation, a CD4 T cell can differentiate into one of several effector subsets (we focused on five, but an additional two subsets have recently been characterized). What are the 5 subsets of CD4 T cells that we focused on? What determines the CD4 subset that a naïve T cell will differentiate to?

The subsets are T helper 1 (TH1) cells, T helper 2 (TH2) cells, T follicular helper (TFH) cells, T helper 17 (TH17) cells, T regulatory (Treg) cells. (TH22 cells and TH9 subsets have also recently been characterized). The subset that a naïve T cell will differentiate into is largely determined by the cytokines that it receives at the time of activation. (The cytokines that are delivered to the CD4 T cell upon activation depend on the type of infection. For example, a dendritic cell will mature when a PAMP binds to one of its PRRs, and the specific PRRs activated will influence the cytokines that are subsequently released.

What is the function of TFH cells? (We will look at their function in more detail in chapter 9).

They activate B-2 cells and promote somatic hypermutation and class switching (see chapter 9 study questions for more detail).

a. What is the major function of TH1 cells?

They activate macrophages to become more effective at phagocytosis. Macrophages initially circulate in tissues in a downregulated state. Often, macrophages can adequately take up and break down material without the need to become upregulated. However, sometimes they need to be upregulated to become more effective at phagocytosis. For example, some pathogens (such as M. tuberculosis, P. jerovecii and Toxoplasma), have evolved to replicate inside macrophage endosomes, and un-activated macrophages are unable to clear the infection

What is the function of Treg cells?

They are anti-inflammatory and function to suppress the activity of other T cell subsets to prevent immune responses against self-antigens and other harmless antigens. They are also involved in terminating an immune response and bringing it to an end once an infection has been cleared, and the anti-inflammatory cytokines they secrete can promote repair of damaged tissue following the immune response

What is the function of TH17 cells?

They enhance the neutrophil response to infections with extracellular bacteria and fungi. They release cytokines that act on other cells at the infection site to release chemokines that recruit neutrophils

What is the function of gamma:delta T cells? How do they differ from alpha:beta T cells in the types of antigen that they recognize? Why are they often described as being 'innate-like' immune cells?

They function in the maintenance of tissue integrity, i.e., they respond to stressed/damaged cells and promote tissue repair. They have a much more limited receptor repertoire than α:β T-cells. Rather than directly recognizing pathogen antigens, they typically recognize antigens that are produced when a cell is under stress as a result of infection (or other situation resulting in cell stress). They also recognize their antigens directly without the need for MHC molecules. They are described as being innate-like because of their more limited receptor repertoire and because they act early during an immune response: they can respond immediately upon detecting their antigen unlike alpha-beta T-cells, which take several days to become activated.

What is the function of TH2 cells?

They help with defense against helminth parasites. They promote immune responses mediated by mast cells and eosinophils, and they promote B cell class switching to the IgE antibody class (this class functions in defense against parasites and type I allergic reactions). They also produce cytokines that promote body responses intended to flush out the parasite, such as increased epithelial cell turnover, increased mucus production, smooth muscle contraction and increased permeability of blood vessels (which causes vomiting and diarrhea)

Following binding of antigen to B-cell receptor, which area does the B-cell go to to encounter its conjugate TFH cell?

To the boundary region between the B cell/T cell areas. Following T cell activation in the Tcell area, activated TFH cells also move to the boundary region to meet the B-cells.

What symptoms would you expect in a patient with a severe T cell deficiency, such as severe combined immunodeficiency syndrome (SCID) or AIDS?

Without T-cells, the body effectively does not have an adaptive immune system as T-cells function in all aspects of adaptive immunity. Patients without functional T cells are extremely susceptible to all types of infections that wouldn't be a problem for healthy individuals. Individuals with SCID die early in life without treatment. Infections that would not cause a problem in healthy individuals become life-threatening in patients with defective T cell functions

For any particular antigen, there may only be about one in every million T-cells that can recognize the antigen. During an infection, is it likely that antigen specific T-cells will be activated?

Yes, T-cells circulate very efficiently through secondary lymphoid tissues and sample large numbers of dendritic cells presenting antigens. For a given antigen, antigen specific T-cells are likely to detect the antigen and become activated within a couple of days.

How is the adaptive immune system able to respond more rapidly and efficiently during a secondary immune response compared to a primary immune response? To answer this question, discuss a) the number of antigen-specific memory cells during a secondary immune response versus the number of antigen-specific naïve cells during a primary immune response, b) antigen-specific antibody and effector memory T cells already in circulation, c) the affinity and class of immunoglobulin during the secondary response versus the primary response, d) the speed of activation of memory cells versus naïve cells, and e) the preferential activation of memory B-cells over new naïve B-cells.

a) During the primary response, activated T cells and B cells underwent proliferation, and some cells differentiated to memory cells. Therefore, for every one initial antigen specific naïve B cell/T cell, there are many-fold more antigen specific memory B cells/T cells. Therefore, upon subsequent exposure to the pathogen, there will be more antigen specific lymphocytes able to respond. b) Long-lived plasma cells continue to secrete a low level of antigen-specific antibody after the primary infection. Upon subsequent infection by the same pathogen, protective antibodies are already in circulation to act immediately. Effector memory T cells are already differentiated and circulate in tissues ready to respond immediately when they encounter their antigen again. c) B memory cells have already undergone affinity maturation and class switching, so they have high affinity, class switched receptors. Therefore, upon subsequent encounter with a pathogen, it will take less antigen to activate memory B cells as their receptors are more sensitive, so they will be activated sooner than naïve B cells. Upon activation, some memory B-cells will immediately differentiate to plasma cells that secrete higher affinity, class switched antibody (which is more effective than the low affinity IgM, which is initially secreted during a primary response). Affinity maturation continues throughout the secondary immune response. d) As mentioned in (c), B cell receptors have a higher affinity for antigen, so they will be activated sooner in the course of an infection. Central memory T cells are also more readily activated compared to naïve T cells (the receptor affinity hasn't changed, but they have been shown to be less reliant on co-stimulation), so they will be activated sooner in the course of an infection. e) Memory B-cells that secrete more effective high affinity, class switched antibody are preferentially activated over new naïve B-cells that would secrete lower affinity, IgM antibodies, which are less effective (see Q5).