Immunology Exam 3

Multiple choice: Most effector T cells migrate out of secondary lymphoid organs and into tissues to exert their function. In which of the cases shown in Figure Q9.25 will the TH1 effector cell undergo long-lived interactions with its target cell, an infected macrophage? Assume all of the target cells shown below are infected with the pathogen recognized by the specific TH1 cells.

A

CXCR5 is the receptor for the chemokine CXCL13, secreted by follicular stromal cells and follicular dendritic cells in the B cell zones (i.e., lymphoid follicles) of secondary lymphoid organs. A conditional knockout mouse in which CXCR5 was specifically deleted only in T cells would have:

A defect in T cell-dependent antibody responses

Patients with the disease X-linked lymphoproliferative syndrome (XLP) lack expression of the small adapter protein SAP, which associates with receptors of the SLAM family. One characteristic of this disease is an inability of cytotoxic T cells to control infections with a virus, Epstein-Barr virus (EBV), that replicates in B cells. This defect in control of EBV results from:

A defect in adhesion of cytotoxic T cells to EBV-infected B cells

Allergic airway inflammation can be induced in mice by immunizing them with an allergen that produces a TH2 effector response, and then challenging the immunized mice with an inhaled form of that allergen. In this disease model, the TH2 effector cells present in the lung respond to the inhaled allergen challenge by producing type 2 cytokines that recruit eosinophils and induce airway inflammation. In addition, a component of this TH2 response is antigen-independent, as shown by the effects of administering a neutralizing antibody along with the allergen challenge. This neutralizing antibody (anti-'X' IgG) has the effects shown in Figure Q11.14. In this experiment, the anti-'X' antibody was shown to inhibit the response of the TH2 cells, and therefore is likely to be:

A neutralizing antibody to TSLP

Leprosy is a disease caused by the intracellular bacterium Mycobacterium leprae, which infects macrophages and replicates in their phagosomes. Human patients with leprosy have a persistent infection of the mycobacteria, as their immune systems are unable to complete eradicate the pathogen. Furthermore, two different forms of the disease have been identified. Some patients have many skin lesions containing a large number of bacteria with little inflammatory response. This is the very disfiguring form of the disease, and is known as lepromatous leprosy. In other patients, few skin lesions and only occasional bacteria are observed, and the skin lesions are accompanied by a robust inflammatory response. These patients have the form of the disease known as tuberculoid leprosy. If one examined a skin biopsy from a patient with tuberculoid leprosy, one would expect to see:

A substantial number of granulomas

In humans, IgA is produced in copious amounts, estimated to be a rate of 3 g/day. Nearly all of the IgA secreting plasma cells are found in the gastrointestinal (GI) tract where the secreted IgA is transported across the GI epithelium into the lumen of the gut. There, this antibody protects the GI epithelium against intestinal pathogens. In contrast, none of the GI resident long-lived antibody secreting cells produce antibodies of the IgG class. The differential localization of long-lived antibody secreting cells producing IgA compared to those producing IgG is likely due to:

A. Their priming and differentiation in mucosal lymphoid organs

The mucosal immune system provides protection for a vast area of the body and contains three-quarters of all the lymphocytes in the body. A key feature of the mucosal immune system is its:

Ability to avoid responding to the large numbers and differing species of commensal microbes

Patients receiving hematopoietic stem cell transplants often suffer from graft-versus-host disease (GVHD), involving immune-mediated damage to the gastrointestinal (GI) tract. The symptoms of GVHD include nausea, vomiting, diarrhea, and abdominal cramping due to epithelial cell apoptosis and inflammatory leukocyte infiltration into the GI epithelium. One proposed treatment has been tested in mouse models of GVHD for potential therapeutic benefit. This treatment is:

Administration of IL-22

The vaccine to Haemophilus influenzae type b is called a conjugate vaccine. It is composed of the tetanus toxoid protein conjugated to the capsular polysaccharide of the H. influenzae type b bacteria. When used to vaccinate infants, the antibody response generated by this vaccine would include:

Antibodies to the bacterial polysaccharide and the tetanus toxoid

In addition to Peyer's patches that resemble systemic lymph nodes, the intestinal epithelium also contains several thousand isolated lymphoid follicles. Unlike the organized secondary lymphoid tissues in the mucosal immune system, these lymphoid follicles:

Are found only in the intestinal epithelium, and not in other mucosal epithelia

In a second experiment, the isolated splenic and lamina propria macrophages were treated with LPS and then incubated with the protein antigen, chicken ovalbumin. CD4 T cells specific for a peptide of ovalbumin (OVA) bound to MHC class II where then incubated with each population of macrophages, and three days later, the culture supernatants were analyzed for IL-2 and IFN-y production. Which of the graphs most likely represent the results of this experiment?

B

In germinal centers, proliferating B cells undergo a process called somatic hypermutation, in which mutations are introduced into the V regions of the antibody heavy and light chain genes. When this process is complete after several weeks, the overall affinities of the antibodies produced are greatly increased compared to those present early in the primary response. The somatic hypermutation process leads to increased antibody affinity because:

B cells making higher affinity antibodies receive more help from Tfh cells

A set of mice are each immunized with one of the following as shown in Figure Q11.20. Mouse A is immunized with tetanus toxoid protein. Mouse B is immunized with the Haemophilus influenzae type b polysaccharide antigen. Mouse C is immunized with a conjugate of the diphtheria toxoid protein linked to H. influenzae type b polysaccharide. Mouse D is left unimmunized (naive). Four weeks later the spleen cells from each mouse are isolated, and B lymphocytes and T lymphocytes from each spleen cell population are purified. When mixed together in culture together with a conjugate antigen of the tetanus toxoid protein linked to the to H. influenzae type b polysaccharide, which combination of spleen cells would generate a memory B cell response?

B lymphocytes from mouse C plus T lymphocytes from mouse A

Purified naive T cells isolated from a T-cell receptor transgenic mouse represent a homogeneous population of cells with specificity for a single known peptide:MHC complex. This specific peptide:MHC complex can be purified and formed into multivalent complexes, such as peptide:MHC tetramers. When the naive T cells are stimulated with their 'antigen' in the form of these peptide:MHC tetramers, the T cells show activation responses, including the up-regulation of genes that are induced within several hours after T-cell receptor stimulation. However, these activated T cells fail to undergo robust proliferation, and the majority of cells die after 3-4 days in culture. T cell proliferation and survival could be greatly augmented by addition of:

B7 ligands for CD28

Eosinophils are a subset of granulocytes that normally reside in the circulation. When activated, these cells secrete toxic compounds that are a key component in the eradication of helminthic parasite infections. Eosinophils are recruited to sites of parasite infections by:

CCL11 produced by TH2 cells

A T cell line growing in culture is subjected to a chemical mutagen, and individual mutant lines are derived from this population. The individual mutant cell lines are each screened for their ability to proliferate in response to stimulation with antibodies to the T-cell receptor plus CD28 (anti-CD3 + anti-CD28). In addition, the cells are treated with varying doses of added IL-2, and three days later, T cell proliferation is measured by 3H-thymidine incorporation (cpm). The data for one mutant line and the wild-type control are shown in Figure Q9.16.

CD25, also known as the IL-2 receptor alpha chain

Studies show that about 50-100 different B cells initially seed each germinal center (d7 post-infection). These different B cells are represented by different colored circles in a white oval (germinal center) in Figure Q10.9. Which of the choices shown best represents the B cell population that would be found in the same germinal center approximately two weeks later?

D

9.9

Dendritic

To generate a vaccine to pertussis toxin, a heat-killed preparation of Bordetella pertussis (the bacteria that produce pertussis toxin) is mixed with a purified preparation of the inactivated toxin protein. The mixture is then injected subcutaneously into mice. In an effort to enhance the antibody response to the toxin, a group of test mice is depleted of all their dendritic cells immediately prior to immunization. However, instead of enhancing the antibody response, the dendritic cell depletion nearly eliminated the anti-toxin antibody response because:

Dendritic cells are needed to activate naive CD4 T cells, which can then help the B cells produce anti-toxin antibody.

Following their activation, naive CD4 T cells differentiate into one of several subsets of effector T cells. This developmental choice is determined by which specific cytokines the T cells are exposed to during their activation; in turn, the cytokines that are produced will reflect the nature of the infecting pathogen. In order for this system to be flexible enough to produce all five effector CD4 subsets (TH1, TH2, TH17, TFH, and iTreg):

Each naive CD4 T cell must express all of the STAT proteins.

Each subset of effector T cells produces a distinct array of secreted factors known as cytokines. One common feature of nearly all effector T cell responses is the rapid production of increased numbers of macrophages, granulocytes, and dendritic cells from the bone marrow. This response occurs due to:

Effector T cell production of GM-CSF that traffics to the bone marrow

When T cells are activated by recognizing peptide:MHC complexes on dendritic cells in the lymph node, they up-regulate the receptor CD69. For T cells expressing a given T-cell receptor, the initial strength of the T-cell receptor signal can be modulated by varying the number of peptide:MHC complexes on the dendritic cells, or by varying the affinity with which the T cell-receptor binds to the peptide:MHC complexes. As a result, T cells stimulated with stronger T-cell receptor signals will maintain high expression of CD69 for one or two days longer that if those same T cells were stimulated with weaker T-cell receptor signals. Therefore, T cells stimulated with weaker T-cell receptor signals are likely to:

Egress from the lymph node 1-2 days earlier than T cells stimulated with stronger T-cell receptor signals

While CD28 co-stimulation is important for the initial activation of naive T cells, other co-stimulatory molecules function at later stages of the T cell response. Several of these other co-stimulatory molecules are members of the TNF-receptor family, and function by activating the transcription factor, NFB. Therefore, stimulation of these co-stimulatory TNF-receptors on activated T cells is likely to:

Enhance T cell survival

At early timepoints following an infection, examination of lymph node CD4 T cells responding to the pathogen would show a heterogeneous population of cells representing several different effector lineages. Likewise, the cytokines produced by these cells would include IFN, IL-4, and possibly others. However, approximately one week later at the peak of the T cell response, the pathogen-specific CD4 T cell population would be largely homogeneous in their production of a single effector subset cytokine profile. This change comes about due to:

Enhanced differentiation of newly activated CD4 T cells into one effector subset

Secretory IgA produced in the epithelium of mucosal surfaces has several functions in protective immunity. Among these are neutralization of pathogens or toxins in the gastrointestinal tract lumen or in epithelial cell endosomes, neutralization of pathogens or toxins that cross the epithelial barrier, and transport of pathogens or toxins across M cells for delivery to lamina propria dendritic cells. All of these functions share the common feature that they:

Fail to induce local inflammation in the gastrointestinal epithelium

12.5 True/False: Oral inoculation with rotavirus, an intestinal pathogen, induces adaptive immune responses that are initiated in gut-associated lymphoid tissue, such as mesenteric lymph nodes and Peyer's patches. The rotavirus-specific effector T cells that are generated in this response are never found in the circulation, but home directly from the lymphoid tissue to the epithelium without ever leaving the intestinal environment.

False

In a lymph node, nTreg cells are able to inhibit the responses of other T cells in their vicinity. This inhibition is specific, as the nTreg cell and the naive T cell must share the same antigen specificity.

False

Naive T cells scan the dendritic cells in the cortical region of the lymph node as they migrate. The initial encounter of T cells with dendritic cells is mediated by interactions between the T-cell receptor and the peptide:MHC complexes on the dendritic cell.

False

The kinetics of a typical CD8 T cell response to an acute virus infection in mice is shown in Figure Q11.18. In this example, the virus is cleared by ~day 7 post-infection, and starting at ~day 10 post-infection, the majority of the virus-specific CD8 T cells die. The death of these virus-specific CD8 T cells is caused by:

Fas-induced death or cytokine withdrawal

Some individuals with repetitive exposure to high doses of Schistosoma mansoni develop resistance to re-infection by this helminthic parasite. In contrast, other individuals remain highly susceptible. Population studies showed that resistant individuals had increased numbers of circulating eosinophils in their blood compared to susceptible individuals, and further, that these eosinophils had increased levels of:

FcRII, the low affinity IgE receptor

IPEX syndrome is a genetic disease due to mutations that disrupt the function of an important transcription factor expressed in subset of CD4 T cells. Individuals with this disease generally begin showing symptoms shortly after birth. This disease is often fatal. One of the most prominent symptoms of IPEX is severe gastrointestinal inflammation accompanied by severe diarrhea. This transcription factor is most likely:

FoxP3

Macrophages were isolated from the spleen or the intestinal lamina propria, and stimulated in vitro with the indicated TLR ligands. Twenty-four hours later, the culture supernatants were tested for the amounts of IL-10, the IL-12p40 subunit (shared between IL-12 and IL-23), and for IL-12, and the results are shown in Figure Q12.9.

Function as anti-inflammatory cells

Effector caspases are activated downstream of both extrinsic and intrinsic pathways of apoptosis. Consequently, cells lacking one or more of these enzymes show defects in apoptosis. An alternative means of eliminating the activity of an effector caspase would be to:

Generate a form of the pro-caspase with a mutation in the initiator caspase cleavage site

Neutralizing antibodies are effective at preventing infection or toxicity mediated by pathogens or their toxic products. In fact, nearly all vaccines currently in use function by eliciting neutralizing antibodies. One example is the tetanus vaccine, in which neutralizing antibodies are generated against an inactivated form of the tetanus toxin (i.e., the tetanus toxoid). The most important feature of a neutralizing antibody is:

Having high affinity for the antigen

Salmonella typhimurium is a Gram-negative bacterial pathogen that infects its host via the gastrointestinal (GI) tract. Early in infection, the bacteria enter and replicate in gut epithelial cells, where the infection provokes a type 3 response, including the development of TH17 cells, in the GI tract. However, this type 3 response in the GI tract does not eradicate the pathogen, as S. typhimurium has evolved strategies to evade the TH17 response and to spread systemically by infecting and replicating in macrophages. Therefore, a second phase of the immune response is required to completely eliminate the pathogen from the body, as has been demonstrated in mouse models of S. typhimurium infection. These experiments in mouse models likely showed that:

IFN- is required to clear S. typhimurium from the body.

Toxoplasma gondii is a single-celled parasitic protozoan that infects and replicates in macrophages. It is common in the environment, and is transmitted to humans by the ingestion of undercooked meat or by accidental ingestion of the parasite's oocytes from contaminated water or cat litter. Infected individuals with healthy immune systems are generally asymptomatic, and rapidly clear the infection. However, in AIDS patients, infections of Toxoplasma gondii can lead to severe disease and even death. To investigate the immune mechanisms important in controlling Toxoplasma gondii, a mouse model of the infection was developed. Mice were infected with the protozoa at a dose where the majority of the mice survive the infection, and at the same time, were injected with a neutralizing antibody to a cytokine made by T cells (anti-'X' IgG). A second group of mice received the protozoa plus a control IgG antibody, as shown in Figure Q11.10.

IFN-y

While innate immune responses to all types of infections induce local inflammatory responses due to activation of blood vessel endothelial cells, some components of the innate response differ depending on the nature of the pathogen. In the case of intracellular bacterial or protozoan infections, tissue-resident dendritic cells and macrophages produce a cytokine that stimulates ILC cells to produce:

IFN-y

Following an acute virus infection in which the host clears the virus by approximately one week post-infection, a population of virus-specific memory CD8 T cells is maintained and can be detected for months to years post-infection. In mice with a knockout of a single cytokine, virus-specific memory CD8 T cells cannot be maintained, and disappear over time as shown in Figure Q11.23. The most likely identity of the cytokine that is missing in these knockout mice is:

IL-15

Reovirus is an enteric virus that infects mice by adhering to intestinal M cells and then using M cell transport to enter Peyer's patches. Mice that were orally inoculated with reovirus cleared the primary infection, and upon secondary challenge 21 days later, had no detectable virus in their Peyer's patches. In contrast, naive controls that did not receive the primary inoculation had >103 PFU of virus/mg of tissue following oral challenge with virus. The protective response induced by the primary oral inoculation would also be eliminated in:

IgA-deficient mice

Individuals with a genetic polymorphism in the Fc receptor, FcRIIa (CD32), have an increased susceptibility to bacterial meningitis (inflammation of the membranes (meninges) surrounding the brain and spinal cord) caused by the encapsulated bacterium, Neisseria meningitidis. This polymorphism reduces the efficiency with which the phagocytes expressing FcRIIa bind to the constant region of this receptor's target antibody. The reason this FcRIIa-dependent response it the major form of protection against Neisseria meningitidis is because:

IgG antibodies are the major isotype able to diffuse into tissues.

The Bcl-2 protein was first identified based on its overexpression in a subset of B cell lymphomas, where it was shown to promote the resistance of the tumor cells to apoptosis. Subcellular localization experiments would show that Bcl-2 is present:

In the mitochondria where it blocks cytochrome c release

Infections of intracellular pathogens (e.g., mycobacteria, listeria, toxoplasma, viruses, etc.) cause a rise in the numbers of monocytes in the blood, a symptom known as monocytosis. In the cases of these infections, monocytosis is likely caused by:

Increased production of monocytes in the bone marrow induced by TH1 cytokines

Mice lacking IL-15 or the IL-15R chain have substantially reduced numbers of type b IELs, including both : and : T-cell receptor-positive subsets. Normal numbers of type b IELs can be restored in il15-/- mice by cell-type specific expression of IL-15 in:

Intestinal epithelial cells

Infection of mice with the bacterial pathogen, Citrobacter rodentium, elicits a protective immune response in the gastrointestinal tract. This protective response is characterized by two sequential waves of IL-22 production, both induced by IL-23. The early wave of IL-22 production (<day 8 post-infection) is likely produced by:

Lamina propria ILC3 cells stimulated by dendritic cell-produced IL-23

It is well documented that antibody affinities for an immunizing antigen continue to increase upon successive rounds of immunization (i.e., secondary, tertiary, etc.). This is due to the fact that:

Memory B cells can re-enter germinal centers and undergo additional somatic hypermutation.

A mouse is infected with staphylococcal bacteria through a laceration in the skin of its paw. Dendritic cells are isolated from the tissue at the site of infection, and are incubated together with naïve staphylococcal-specific CD4 T cells. Seventy-two hours later, the proliferation of the CD4 T cells is measured as a readout for T cell activation. Surprisingly, the T cell response is quite poor compared to the response observed when the same T cells are mixed with a comparable number of dendritic cells isolated from the draining lymph node of the infected mouse. A comparison of the dendritic cells isolated from the two different sites would reveal:

Much higher levels of MHC and B7 molecules on the lymph node dendritic cells than those from the infected tissue

Antibody-dependent cell-mediated cytotoxicity (ADCC) is an important effector mechanism in immunity to virus infections. This immune pathway has also been exploited for clinical applications. For instance, patients with various disorders, including rheumatoid arthritis and some B cell lymphomas, are treated with an antibody directed at CD20, a surface receptor expressed on all B cells. This antibody leads to the depletion of B cells from the patients by the actions of:

Natural killer (NK) cells

Inflammatory bowel disease (colitis) is a CD4 T-cell mediated disease that can be transferred to naive mice by administration of effector CD4 T cells that home to the gastrointestinal tract and induce inflammation. Simultaneous administration of neutralizing antibodies to IL-12p40 can prevent the disease, as can neutralizing antibodies to IL-23p19. Disease symptoms can be exacerbated by administration of IL-23, but not of IL-12. These data strongly suggest that

Neutralizing antibodies to IL-17 would prevent disease.

Infants born with the immunodeficiency disease X-linked agammaglobulinemia (XLA) have a block in B cell development, and fail to produce mature B cells. As a result, these infants lack the ability to produce antibodies. After birth, babies with XLA first begin to show symptoms of recurrent and persistent extracellular bacterial infections due to common environmental pathogens when they are 4-6 months of age. The reason these infants are healthy for the first 4-6 months after birth is because:

Newborn infants have high circulating levels of maternal IgG at birth.

Wild-type mice infected with one strain of Influenza A virus (PR8) by intranasal inoculation are protected from intranasal infection by a related Influenza A virus (Beijing), a phenomenon known as cross-protection. These infections are generally localized to the upper respiratory tract. Mice with a homozygous single gene defect in 'gene X' have greatly impaired cross-protection to Influenza A-Beijing following immunization with Influenza A-PR8 by the intranasal route. Gene X likely encodes:

Poly Ig receptor

Helicobacter pylori is a human gastrointestinal (GI) pathogen that can lead to a state of chronic GI inflammation in some individuals, and has been linked to gastric ulcers and other diseases. Studies have shown that human mucosal gastric biopsies of infected individuals have dendritic cells producing IL-23, and that human monocytes isolated and cultured from healthy individuals produce IL-23, but not IL-12, in response to stimulation with live H. pylori. Given these findings, which of the following responses would be enhanced in the GI tract of H. pylori-infected individuals compared to uninfected individuals?

Recruitment of neutrophils

Several effector T cell functions are mediated by cell surface molecules on the effector cell interacting with binding partners on the target cells. In the case of the CD40-CD40 ligand interaction, effector CD4 T cells express CD40 ligand, which binds to CD40 target cells. Individuals with a genetic deficiency in CD40 ligand expression show greatly reduced antibody responses, particularly to protein antigens which require CD4 TFH cell interactions with B cells. Another expected defect in these individuals would be:

Reduced activation of macrophages by TH1 cells

The compound LE135 is an inhibitor of the retinoic acid receptor, and blocks signaling through this receptor. In a mouse model of inflammatory bowel disease (IBD), inflammation in the gastrointestinal (GI) epithelium is significantly exacerbated if animals are treated with LE135. Analysis of the CD4 T cell subsets found in the GI epithelium of LE135-treated mice compared to controls with IBD would likely show:

Reduced numbers of iTregs in the LE135-treated mice

IL-10-deficient mice develop spontaneous colitis, a disease due to chronic inflammation in the gastrointestinal (GI) tract. However, when these mice are housed in germ-free conditions, in which they lack all commensal microbes in their GI tract, no colitis was observed. In addition, one would expect germ-free IL-10-deficient mice to also show:

Reduced production of IgG antibodies compared to conventionally housed il10-/- mice

The TNF family of cytokines and their receptors are critical for the development of secondary lymphoid organs, such as the lymph nodes and Peyer's patches. As a consequence, knockout mice lacking expression of LT- fail to develop most of these structures. Reconstitution of irradiated LT--deficient mice with bone marrow stem cells from wild-type mice (e.g., LT--sufficient) would:

Restore the missing follicular dendritic cells but not the missing lymphoid structures in the recipient mice

Salmonella typhimurium is the causative agent of typhoid fever, and infects the host by translocating across the intestinal epithelium. Recent studies have shown that S. typhimurium produces an effector protein called SopB that induces intestinal enterocytes to differentiate into M cells. This is beneficial to the bacteria because:

S. typhimurium gains access to the host by crossing the intestinal epithelium inside M cells.

9.5

Selectins

IL-23 is a cytokine made by macrophages and dendritic cells in response to extracellular bacterial and fungal infections. Mice with a genetic defect in the production of IL-23 are highly susceptible to the gastrointestinal bacterial pathogen, Citrobacter rodentium. Thus, unlike wild-type mice which clear the infection, mice that fail to produce IL-23 succumb to the bacteria and die 1-2 weeks post-infection. Yet, this cytokine does not directly act on the bacteria nor does it function to recruit the granulocytes that are needed to eliminate the pathogen. Instead, IL-23:

Stimulates IL-17 and IL-22 production by ILC3 cells

When mice are born, their intestinal lamina propria lacks TH17 effector cells. These cells develop after birth due to:

Stimulation by antigens derived from commensal microbes that populate the gastrointestinal tract after birth

Initially after an infection, the majority of the T cells present in the tissue at a site of infection are not specific for the infecting pathogen, but over the course of several days, this changes and antigen-specific T cells become enriched at this site. This is because:

T cells do not use their T-cell receptors during extravasation from blood into tissues.

In cell culture experiments, purified B cells expressing IgM can be induced to switch to producing IgE by stimulating them with an antibody to CD40 (a stimulatory antibody) plus the cytokine IL-4. In an individual undergoing an immune response, these signals would normally be provided by:

TFH cells in the germinal center

Wiskott-Aldrich syndrome is an immunodeficiency disease that causes a defect in antibody responses. The most severe defects are in antibody responses to protein antigens, which are dependent on CD4 effector TFH cells providing cytokines to the B cell. The protein defective in individuals with the disease, known as WASp, functions in cytoskeletal reorganization and polarization through its role in promoting actin polymerization. This immune defect could be fixed by a gene therapy approach that restored WASp expression in:

Tcells

Inbred strains of mice often generate highly polarized CD4 T cell responses to specific infections that are dominated by one subset of effector cells. In the case of Balb/c mice infected with the intracellular protozoan Leishmania major, a robust CD4 T cell response is elicited, generating large numbers of L. major-specific T cells; however, this response does not eliminate the pathogen, and instead the mice succumb to the infection. One likely explanation for this finding is:

The CD4 T cell response produces effector cytokines that do not activate macrophages.

IgM antibodies are much more efficient than IgG at activating the complement cascade. However, under certain circumstances, IgG antibodies will activate the complement pathway. One example of a situation in which IgG binding to its antigen will not trigger the complement cascade is when:

The IgG antibodies are neutralizing a bacterial toxin protein by blocking the receptor-attachment site on the toxin.

Mice lacking the poly Ig receptor (pIgR) have an immunodeficiency disease characterized by increased susceptibility to mucosal infections and an increase in the penetration of commensal microbes into the body's tissues. Yet, a genetic deficiency in the production of IgA antibodies is the most common form of human immunodeficiency, and is generally a mild disease and often even asymptomatic. This dichotomy can be explained by:

The ability of pIgR to transport IgM across the gut epithelium

Individuals with the HIV-induced immunodeficiency disease AIDS have a progressive loss in the number of CD4 T cells in their bodies. These patients have a greatly increased rate of life-threatening disease caused by the inability of their immune system to control infections of the intracellular bacterium, Mycobacterium tuberculosis (Mtb). Mtb infects macrophages and then replicates in the cell's phagosomes. The most important immune mechanism lacking in these patients that leads to their increased susceptibility to Mtb is a defect in:

The activation of macrophages by TH1 effector cells

Naive T cells are isolated and left untreated or treated with 'compound X' for 1 hour. Following this, the T cells are incubated with a range of concentrations of a soluble form of ICAM-1 that has been conjugated to a fluorescent dye (soluble-ICAM-1-FITC). Fifteen minutes later, the cells are washed, and the relative amount of fluorescence bound to the cells is measured. The results of this assay are shown in Figure Q9.6.

The chemokine ligand for CCR7

An immunodeficient mouse strain is identified, that has a single gene defect causing its disease. Mice with this defect have greatly impaired responses to protein antigens following subcutaneous immunization and also exhibit severely delays in the kinetics of their antibody responses. Analysis of their lymph nodes revealed profound alterations in the normal architecture, with a lack of organization of distinct T-cell and B-cell zones. A likely candidate for the defect in these mice is:

The chemokine receptor CCR7, which recruits B cells, T cells, and dendritic cells to lymph nodes.

Cytotoxic T cells are rapid killers of infected target cells. Within minutes of the interaction of a cytotoxic T cell with a target cell, the program of apoptosis in the target cell is initiated. This rapid activity is a consequence of:

The expression and packaging of perforin and granzymes in cytotoxic granules prior to target cell encounter

A healthy intestinal mucosa is one in which induced adaptive immune responses to pathogenic infections are balanced by the lack of responses to innocuous food antigens and commensal microbes. This balance is maintained by an array of different subsets of effector T cells and regulatory T cells that reside in the intestinal epithelium and lamina propria. Although these different T cell subsets have diverse patterns of cytokine production and other effector functions, they share:

The expression of gut-homing chemokine receptor, CCR9

Vibrio cholerae causes an acute diarrheal illness that can be fatal if not treated. Several vaccines have been developed in an effort to prevent this disease. The oral cholera vaccine is a mixture of killed Vibrio cholerae bacteria plus additional inactivated cholera toxin protein. Efficacy studies of this vaccine indicate that it prevents 50-60% of the cases of cholera infection observed in non-vaccinated individuals. In contrast, injectable vaccines made from killed bacteria or purified bacterial subunits are substantially less effective at preventing infections. This is likely due to the fact that:

The injectable vaccine fails to elicit gut-homing immune responses.

In the cases of some infections, such as mice infected with adenovirus, the generation of effector cytotoxic CD8 T cell responses needed to clear the infection is dependent on the antigen-presenting dendritic cells receiving stimulation through the CD40 receptor on their surface, a process known as dendritic cell 'licensing'. In this infection system, the dendritic cell would likely receive CD40 receptor stimulation from:

The interaction with a CD4 effector cell expressing CD40 ligand

Secondary lymphoid organs, such as the lymph nodes, spleen, and mucosa-associated lymphoid tissues, each have distinct features that are important for their role in initiating immune responses focused on different anatomical compartments (i.e., the peripheral tissues, the blood, or the gastrointestinal tract, respectively). Yet these organs share some overall structural features, such as distinct T-cell and B-cell zones. One major difference between these organs is:

The mechanism by which antigens or pathogens enter the organ

A mouse is immunized with a single 9 amino acid peptide derived from the influenza virus. This peptide binds to MHC class I and produces an epitope (peptide:MHC complex) recognized by a small number of naive CD8 T cells in the mouse. The peptide is mixed with CpG oligonucleotides that are ligands for TLR-9. Surprisingly, this immunization regimen generates a very poor cytotoxic CD8 effector response to targets coated with this peptide compared to immunization with a preparation of intact heat-killed influenza virus mixed with CpG oligonucleotides. The enhanced cytotoxic T cell response to the peptide observed following immunization with intact viral particles compared to the peptide alone is due to:

The presence of CD4 T cell epitopes in the intact virus

The upper respiratory tract of many individuals is colonized by Streptococcus pneumoniae bacteria. Infections caused by these bacteria, including pneumonia, meningitis, otitis media (ear infections), and sinusitis, are thought to occur in individuals lacking protective antibodies. For many years, IgG was thought to be the major antibody class responsible for protective immunity to S. pneumoniae, due to the ability of anti-bacterial capsule IgG antibodies to opsonize the bacteria and promote phagocytosis. However, in addition to IgG, pneumococcal polysaccharides elicit robust IgA antibody responses. It was traditionally thought that these IgA antibodies functioned in neutralization, by blocking bacterial attachment to mucosal epithelial cells. It is now known that IgA antibodies, like IgG, can function as opsonins, to induce phagocytosis and killing of IgA-coated pathogens. This function of IgA antibodies depends on:

The presence of IgA-specific Fc receptors on neutrophils and macrophages

Immunological memory in humans has been examined by assessing responses in individuals who were given the vaccinia virus to induce immunity against smallpox. Antiviral CD4 and CD8 T cell responses could be detected many years after the vaccinia immunization, but declined with an estimated half-time of about 10 years. In contrast, antiviral antibody responses were maintained at a relatively constant level, with a barely detectable decline over decades. The persistence of antiviral antibodies for years after immunization is likely due to:

The presence of long-lived antibody secreting plasma cells

Unlike somatic hypermutation, class switching occurs in discrete sequence regions upstream of the immunoglobulin heavy chain coding sequences (called switch regions). One key element in directing the enzyme AID to a specific switch region is the opening of the DNA duplex combined with polymerase stalling during active transcription in that region. A second key feature of directing AID to a specific switch region is:

The processed RNA from the switch region guides AID to this site in the DNA

In response to an intracellular bacterial or viral infection, effector TH1 cells, macrophages, NK cells, and CD8 cytotoxic effector cells are all recruited to the site of infection. The coordinated recruitment of all of these cell types is orchestrated by:

The shared expression of chemokine receptors on these different cell types

Analysis of human milk from lactating mothers shows that it contains IgA antibodies against infections that were recent (<3 weeks earlier) and those from the distant past (>1 year). These antibodies are directed against a host of organisms, including viruses, such as enteroviruses, herpes simplex viruses, respiratory syncytial virus, rubella, reovirus, and rotavirus. In addition, IgA antibodies against many bacteria are found in human milk, including those reactive to E. coli, Shigella, Salmonella, Campylobacter, Vibrio cholerae, H. influenzae, S. pneumoniae, Clostridium difficile, C. botulinum, and Klebsiella pneumoniae. IgA antibodies to the parasite Giardia and the fungus, Candida albicans, are also seen in human milk. Since most of these infections were localized in the gastrointestinal tract of the mother, these IgA antibodies ended up in breast milk by:

The trafficking of gut-primed activated B cells from the mother's circulation into the lactating milk gland.

Cytotoxic effector T cells also produce inflammatory cytokines such as IFN- and TNF- when their T-cell receptor recognizes peptide:MHC on a target cell. One effect of this cytokine secretion is to enhance the ability of CD8 effector T cells to recognize and kill other infected cells in the nearby vicinity. This enhanced activity is due to:

The up-regulation of MHC class I protein expression by IFN-

The process of somatic hypermutation of antibody V regions sequences is initiated by the enzyme AID. This enzyme targets cytidine residues in the DNA sequence that are normally part of a G:C pair in the double-stranded DNA. Yet the hypermutation process generates mutations at both G:C and A:T base pairs of the original sequence because:

There are two different pathways of repair target, one targeting G:C and one targeting A:T base pairs.

A mouse is immunized with the tetanus toxoid protein (inactivated toxin) in adjuvant. One week later, the entire population of splenic B cells are isolated from the mouse and mixed with tetanus toxoid-specific CD4 TFH cells plus the purified tetanus toxoid protein. Four days later, the total number of B cells in the culture and the number of tetanus toxoid-specific B cells are determined and compared to the starting population on the day of isolation. The results are shown in Figure Q10.1.

They are the only B cells presenting the tetanus peptide to the TFH cells.

Studies in mice have shown that resident memory cells (TRM) most often take up permanent residence in the tissue where the initial infection that produced those memory cells occurred. In this location, they are poised to respond rapidly should that infection re-occur in that same location. In contrast, central memory cells (TCM) are primarily found in secondary lymphoid organs, where they can be activated to proliferate and differentiate into effector cells when stimulated by antigen-bearing dendritic cells following re-infection. The third subset of memory cells, effector memory cells (TEM), are recirculating cells that can readily enter tissues at sites of inflammation or infection and are poised to rapidly respond to re-infection. The subset of TEM cells provides an important component of protective immunity to re-infection by the same pathogen because:

They express the integrin E7 that binds to integrin ligands expressed on epithelial cells.

The W/Wv mouse strain is heterozygous for two different alleles of the gene encoding the growth factor receptor, c-kit, an important receptor expressed on hematopoietic progenitor cells in the bone marrow. The major defect in these mice is the absence of single lineage of hematopoietic cells. When these mice are challenged with larval Haemaphysalis longicornis ticks, they fail to become resistant to the ticks, in spite of generating high titers of anti-tick IgE antibodies. The cell type missing in the W/Wv mice is most likely:Natural Killer (NK) cells

Tissue-resident mast cells

Strep throat is commonly caused by group A Streptococcus bacteria. A common symptom of strep throat is the presence of swollen lymph nodes in the neck. This symptom usually peaks about 2-4 days after the onset of the infection, and is due to:

Trapping and activation of antigen-specific lymphocytes in the lymph nodes of the neck

Cytotoxic T cells that lack expression of perforin are more defective in killing target cells than those that lack granzymes.

True

The TACI receptor on B cells, which binds to BAFF and APRIL, is important in IgA antibody secretion by B cells in the gastrointestinal lamina propria.

True

The generation of optimal CD8 T cell memory following a primary infection requires CD4 T cell help for the responding CD8 T cells. This requirement for CD4 T cell help would not be completely replaced by supplying high levels of the cytokine IL-2 during the primary CD8 T cell response.

True

Unlike innate immune responses, adaptive immune responses are initiated in secondary lymphoid organs. However, the innate immune response to an infection in a tissue has a pivotal role in inducing T-cell responses in the nearest lymph node by activating tissue dendritic cells and inducing their migration to the lymph node.

True

Many virus infections induce robust production of type I interferons, IFN- and IFN-. One example is the herpes simplex virus-1 (HSV-2), one of the most common sexually transmitted diseases in the US. Experiments that investigated the immune response to HSV-2 using a mouse model demonstrated essential roles for the DNA sensing Toll-like receptor, TLR9, and its downstream signaling adapter, MyD88, in the production of type I interferons following HSV-2 immunization. The type I interferon response to HSV-2 would be restored in Tlr9-/- mice by transferring into these mice wild-type:

Up-regulate MHC class II and B7 molecules to amplify CD4 T cell responses in the lung

The germinal center is a region within the secondary B cell follicle where sustained B cell proliferation and differentiation take place. The processes of B cell proliferation and differentiation, including affinity maturation and class switching, require periodic interactions of the germinal center B cells with CD4 TFH cells. These periodic interactions between the B cells and TFH cells can occur:

When B cells cycle between the dark zone and the light zone of the germinal center

Cytotoxic granules released from cytotoxic T cells contain proteins that enter target cells and induce apoptosis. Do any of the mechanisms of apoptosis induction by cytotoxic effector T cells rely on the protein APAF-1? If so, which pathway?

Yes - Intrinsic pathway

In some infectious diseases, antibodies specific for the pathogen are not essential for clearing a primary infection with that pathogen, but are essential in preventing re-infection by the same pathogen. This protective role of pathogen-specific antibodies is not useful for any clinical applications.

false

Once B cells begin secreting antibodies, they cease dividing and have a life-span of only a few days.

false

Two different vaccines have been developed that protect vaccinated individuals against pneumococcal disease, a bacterial infection that causes pneumonia, meningitis and sepsis (blood stream infection). This disease is caused by the bacteria, Streptococcus pneumoniae. One vaccine, PPSV23, is a mixture of polysaccharides isolated from 23 different serotypes of S. pneumoniae. The second vaccine, PCV13, is a conjugate vaccine made from polysaccharides of 13 different serotypes of the bacteria conjugated to diphtheria toxoid (inactivated toxin protein). The PPSV23 vaccine is only given to adults, whereas infants and small children are given PCV13. This is because:

infant B cells are immature and don't respond to TI-2 antigens

Mice deficient in the enzyme MMP7, that cleaves prepro--defensin to the active -defensin, show an increased susceptibility to the enteric pathogen, Salmonella typhimurium. The cell type in the gastrointestinal (GI) epithelium most likely to express the highest levels of MMP7 is:

paneth cells

Nitric oxide and superoxide radicals are toxic compounds that induce substantial DNA damage. When released by activated M1 macrophages, these compounds cause damage to microbial pathogens and may also cause damage to host cells in the vicinity.

true

Oral tolerance to food antigens and immune tolerance to gut microbiota share the property that foreign antigens encountered in the gastrointestinal (GI) tract—food and commensal microbes, respectively—do not elicit immune effector responses. Yet, these processes differ in that commensal microbes will still elicit protective adaptive immune responses if they cross the GI epithelium and enter the body.

true