CH. 8
8-2 Why are dendritic cells so important in adaptive immune responses? Explain what they do.
Dendritic cells engulf, process and then transport antigens to a nearby secondary lymphoid tissue, such as lymph nodes, where they then encounter antigen-specific T cells, which then differentiate into effector T cells. Effector T cells are then able to leave the secondary lymphoid tissue and travel to the site of infection and perform their particular effector response to eradicate the infection
8-5 Unlike innate immune responses, which can begin within hours of the onset of an infection, adaptive immune responses involving T cells usually take several days. What accounts for this delay between the initiation of an infection and the engagement of an adaptive immune response?
First, antigen needs to be transported to a nearby secondary lymphoid tissue, processed, and presented by antigen-presenting cells to naive CD8 or CD4 T cells for T-cell priming. Second, the number of T cells specific for a given pathogen will be only around 1 in 10,000 to 1 in 100,000 (10-4 to 10-6) of the circulating T-cell repertoire; thus it can take some time before the relevant T cells circulating through the secondary lymphoid tissues reach the tissue containing the antigen that will activate them. Finally, it takes several days for an activated T cell to proliferate and differentiate into a large clone of fully functional effector T cells.
8-11 Why are Toll-like receptors (TLRs) important for adaptive immune responses?
Stimulation of TLRs on dendritic cells by pathogen components induces the expression of chemokine receptor CCR7 on the dendritic cell. This enables dendritic cells laden with pathogen antigens to migrate from the site of infection to the nearest draining lymph node in response to chemokines produced by the lymph node. Stimulation of TLRs and other receptors on dendritic cells and macrophages also induces the expression of B7 co-stimulatory molecules, which makes these cells into professional antigen-presenting cells that are able to activate naive T cells.
8-16 Which of the following is associated with immature dendritic cells in the skin before their activation? a. Toll-like receptors b. CTLA4 c. CCR7 d. DC-SIGN e. ICAM-3.
a
8-19 Naive lymphocytes homing to lymphoid tissue use _____ to bind to CD34 and GlyCAM-1 on high endothelial venules. a. L-selectin b. CD2 (LFA-2) c. ICAM-1 d. CCL21 e. CD28.
a
8-21 An adhesion molecule called _____ is expressed exclusively on activated dendritic cells and binds to _____ on naive T cells in the T-cell areas of secondary lymphoid tissue. a. DC-SIGN; ICAM-3 b. CD2; LFA-3 c. MHC class II; T-cell receptor d. L-selectin; GlyCAM-1 e. ICAM-1; LFA-1.
a
8-25 The primary effect of inositol trisphosphate (IP3) during T-cell activation is to _____. a. cause an increase in cytosolic calcium concentration b. activate phospholipase C-γ c. activate a MAP kinase cascade d. facilitate the differentiation of immature effector T cells e. align the microtubule-organizing center toward the antigen-presenting cell.
a
8-28 All of the following statements regarding interleukin-2 (IL-2) or its receptor are true except _____. a. The low-affinity IL-2 receptor is a membrane-bound heterodimer composed of α and β chains. b. IL-2 production increases approximately 100-fold if a co-stimulatory signal is delivered. c. T-cell proliferation occurs upon binding of IL-2 to the high-affinity IL-2 receptor. d. The high-affinity IL-2 receptor is assembled after T-cell activation. e. Rapamycin is an immunosuppressive drug that inhibits signaling of IL-2 through the IL-2 receptor.
a
8-33 All of the following indicate correct intermolecular associations except _____. a. Janus kinases (JAKs): serglycin b. L-selectin: GlyCAM-1 c. VLA-4: VCAM-1 d.JAKs: signal transducer e. CD40: CD40 ligand.
a
8-45 Which of the following is not produced by TH17 cells? a. ICOS (inducible T-cell co-stimulator) b. IL-17 c. CD4 d. IL-21 e. STAT3
a
8-54 In the absence of a co-receptor (CD4 or CD8 for T helper cells or cytotoxic T cells, respectively), T cells require _____ specific peptide:MHC complexes on the antigen-presenting cell compared with interactions involving a co-receptor. a. more b. fewer c. the same number of.
a
8-57 Expression of IFN-γ is induced in a CD4 TH1 cell under the direction of the transcription factor ______. a. T-bet b. FoxP3 c. AP-1 d. GATA-3 e. NFAT.
a
8-61 Signal transducers and activators of transcription (STATs) are _____ that are phosphorylated by _____. a. transcription factors; JAKs b. protein kinases; other STATs c. cytokine receptors; JAKs d. cytokines; cytokine receptors e. transcription factors; Lck.
a
8-8 Match the molecule in column A with its ligand in column B. Column A ___a. B7 ___b. CD2 ___c. L-selectin ___d. ICAM-1 ___e. CCR7 ___f. ICAM-3 Column B 1. sialyl-LewisX carbohydrate of CD34 and GlyCAM-1 2. CCL21 and CCL19 3. LFA-3 4. CD28 5. LFA-1 6. DC-SIGN
a - 4 b - 3 c - 1 d - 5 e - 2 f - 6
8-13 Dendritic cells take up, process or present antigen by all of the following routes except _____. a. receptor-mediated endocytosis of bacteria b. macropinocytosis of bacteria or viruses c. uptake of viruses using Toll-like receptor TLR9 d. cross-presentation from the MHC class II pathway to the MHC class I pathway e. cross-presentation from incoming infected dendritic cells to healthy resident dendritic cells in secondary lymphoid tissue f.delivery of viral peptides from cytosol to endoplasmic reticulum during viral infection.
a, b, d, e
8-51 Clonal expansion and differentiation of naive T cells to effector T cells depends on the activation of the transcription factor(s) _____ through a ZAP-70-mediated signal transduction pathway. (Select all that apply.) a. AP-1 b. IL-2 c. NFκB d. NFAT e. Ras.
a, c, d
8-36 Which of the following cytokines is not secreted by TH2 cells? (Select all that apply.) a. IFN-γ b. IL-4 c. IL-5 d. IL-10 e. TGF-β f. lymphotoxin (LT).
a, f
8-18 Match the term in column A with its counterpart in column B. Column A ___a. immunoreceptor tyrosine-based activation motifs (ITAMs) ___b. signal transducers and activators of transcription (STATs) ___c. immunological synapse ___d. VLA-4 ___e. CD40 Column B 1. when phosphorylated, it translocates as a dimer to the nucleus and facilitates expression of target genes 2. facilitates binding of effector T cells to activated endothelium 3. on cytoplasmic tails of CD3 proteins used for transmitting activation signals 4. a receptor on macrophages that facilitates killing of intravesicular bacteria 5. region of contact containing adhesion molecules and other cell-surface receptor-ligand pairs between a lymphocyte and its target cell
a—3 b—1 c—5 d—2 e—4
___a. mature dendritic cells 1. produce type-1 interferons during viral infections ___b. TH17 cells 2. facilitate antibody production and isotype switching ___c. plasmacytoid dendritic cells 3. express the T-bet transcription factor ___d. TH1 cells 4. possess elaborate finger-like processes that interact with T cells ___e. TFH cells 5. involved in neutrophil recruitment to infected tissues
a—4, b—5, c—1, d—3, e—2
8-20 The co-stimulatory molecule _____ on professional antigen-presenting cells binds _____ on the surface of naive T cells. a. DC-SIGN; ICAM-3 b. B7; CD28 c. ICAM-1; LFA-1 d. MHC class II; T-cell receptor e. MHC class II; CD4.
b
8-23 All of the following are included in the central supramolecular activation complex (c-SMAC) except _____. a. CD4 or CD8 b. ICAM-1 c. CD28 d. T-cell receptor e. PKC-θ.
b
8-34 During cytokine signaling, _____ translocate(s) to the nucleus and direct(s) the upregulation of gene expression. a. perforin b. STATs c. CD40 ligand d. TGF-β e. CXCL2.
b
8-38 The release of lytic granules from cytotoxic T cells is aimed specifically at infected target cells while preserving the integrity of neighboring, uninfected cells. This is best explained by the observation that _____. a. only target cells bearing appropriate peptide:MHC class I complexes are susceptible to necrosis b. redistribution of lytic granules in the T cell delivers them to confined areas on the target cell in contact with the T cell c. regulatory T cells deliver survival signals to uninfected neighboring cells that renders them resistant to cytotoxins d. the amount of cytotoxins in a given cytotoxic T cell is so limited that only the cell closest to the T cell will succumb to the effects of perforin and granzyme e. uninfected cells are highly resistant to the effects of cytotoxins.
b
8-41 Identify the mismatched pair. a. TFH cells: Bcl6 b. TH1: GATA3 c. TH1 cells: IFN-\gamma d. TH2: IL-4 e. Treg: TGF-\beta
b
8-52 Fos, a component of the transcription factor AP-1, is activated during T-cell signaling by a process involving a GTP-binding protein called _____. a. inositol trisphosphate b. Ras c. protein kinase C-θ d. Lck e. ZAP-70.
b
8-55 Which of the following is a protein tyrosine kinase involved in T-cell activation culminating in T-cell proliferation and differentiation? a. AP-1 b. ZAP-70 c. NFκB d. NFAT e. calcineurin.
b
8-65 Parents who were distantly related to each other brought their 11-week-old infant Kristen to the emergency room after she had a seizure accompanied by a persistently high fever and running nose. Her liver and spleen were palpable (hepatosplenomegaly). Laboratory tests revealed abnormally high levels of lymphocytes, and of the cytokines IFNγ, TNF-α, and IL-6. Conversely, levels of hemoglobin and platelets were abnormally low. Bone marrow aspiration showed the presence of macrophages containing phagocytosed red blood cells and numerous large granular lymphocytes. Molecular analysis was carried out to confirm the physician's suspicion of a congenital immunodeficiency. A frameshift mutation in the perforin gene PRF1 was found on both chromosomes. Kristen was diagnosed with the rare, potentially life-threatening disease known as familial hemophagocytic lymphohistiocytosis (FHL). Cytotoxic and aggressive immunosuppressive chemotherapy was administered followed by a matched unrelated hematopoietic stem cell transplant. Two years later Kristen is a healthy toddler. Which of the following would not be consistent with the etiology of FHL? a. impaired cytotoxic activity of CD8 T cells b. inhibition of transcriptional activators required for IL-2 synthesis c. inability to kill virus-infected cells d. persistent activation of CD8 T cells causing secretion of large amounts of IFN-γ e. IFN-γ activation of macrophages which in turn drives the production of IL-6, TNF-α, and other pro-inflammatory molecules.
b
8-12 Which of the following describes an activated dendritic cell upon arriving in a lymph node? a. located in follicles and medulla of the lymph node b. associated mainly with antigen uptake and processing c. bears highly elaborated finger-like processes called dendrites d. expresses low levels of MHC class II molecules e. carries out apoptosis of lymphocytes.
c
8-24 Talin is best described as a _____. a. protein tyrosine kinase b. transcriptional activator c. cytoskeletal protein d. pro-inflammatory cytokine e. cytokine receptor that associates with Janus kinases (JAKs).
c
8-27 The enzyme that generates diacylglycerol (DAG) and inositol trisphosphate (IP3) from phosphatidylinositol bisphosphate (PIP2) is _____. a. protein kinase C-θ (PKC-θ) b. calcineurin c. phospholipase C-γ (PLC-γ) d. protein tyrosine kinase ZAP-70 e. protein tyrosine kinase Lck
c
8-31 Which of the following statements is false regarding CD8 T cells? a. CD8 T cells have only one effector function, which is cytotoxicity. b. Compared with naive CD4 T cells, naive CD8 T cells have more stringent requirements for co-stimulatory activity. c. Effector CD8 cells require co-stimulation to kill their target cells. d. The most potent antigen-presenting cell for naive CD8 T cells is the dendritic cell.
c
8-37 In a person with lepromatous leprosy, the lesions would contain mRNA for _____. a. lymphotoxin (LT) b. IL-2 c. IL-5 d. IFN-γ e. granulysin.
c
8-42 Which of the following is incorrect regarding sphingosine 1-phosphate (S1P) and its receptor? a. It is a lipid that has chemotactic activity. b. S1P gradients are established in lymph nodes with lowest concentrations in T-cell areas. c. CD69 upregulates S1P receptor expression on the surface of naive T cells. d. S1P is synthesized by all cells.
c
8-43 Which of the following is produced by CD8 T cells? a. IL-10 b. TGF-β c. IFN-γ d. IL-4 e. IL-17
c
8-53 _____ is a second messenger in the T-cell signaling pathway leading to the activation of NFAT. a. diacylglycerol (DAG) b. NFκB c. inositol trisphosphate d. Fos e. Ras.
c
8-59 Tuberculoid leprosy is characterized by a _____-type response in which patients _____. a. TH2; usually survive b. TH2; eventually die c. TH1; usually survive d. TH1; eventually die e. Treg; eventually die.
c
8-6 Macrophages exhibit all of the following characteristics except _____. a. they trap and degrade pathogens in secondary lymphoid organs b. they deliver co-stimulatory signals to naive T cells needed for T-cell priming c. they migrate from sites of infection to nearby secondary lymphoid organs e. they remove and degrade apoptotic lymphocytes from secondary lymphoid tissues f. they reside in both the cortex and medulla of lymph nodes.
c
8-62 The process by which cytotoxic T cells kill their targets involves _____. (Select all that apply.) a. inducing the target cell to undergo necrosis b. inducing apoptosis (programmed cell death) in the cytotoxic T cell c. DNA fragmentation in lengths of multiples of 200 base pairs in the target cell d. shedding of membrane-bound vesicles and shrinking of the target cell e. release of granzyme, perforin, and granulysin by the cytotoxic T cell.
c, d
8-47 Which of the following is a feature of regulatory T cells (Treg)? (Select all that apply.) a. Treg express CD8 and control effector cells by inducing apoptosis. b. Treg express high levels of CD25 (IL-2 receptor α chain) and secrete pro-inflammatory cytokines such as IFN-γ. c. Physical association between Treg and their target cells is mandatory for Treg function. d. By interacting with dendritic cells in secondary lymphoid tissue, Treg prevent the interaction and activation of naive T cells. e. Treg secrete TGF-β and suppress effector T-cell function.
c, d, e
8-35 Which of the following cytokines is secreted by both CD8 T cells and TH1 cells? (Select all that apply.) a. IL-4 b. IL-5 c. IFN-γ d. TNF-α e. IL-13 f. lymphotoxin (LT).
c, f
8-1 Which of the following contributes to the activation of naive T cells? a. neutrophils b. B cells c. macrophages d. dendritic cells e. basophils
d
8-14 Activated T cells express _____, which binds to B7 with 20 times higher affinity than CD28 and results in _____ of T-cell activity and proliferation. a. high-affinity IL-2 receptor; stimulation b. CD40L; suppression c. VLA-4; stimulation d. CTLA4; suppression.
d
8-29 If a non-professional antigen-presenting cell that lacks co-stimulatory molecules presents peptide:MHC complexes to a T cell specific for that peptide, then _____. a. the T cell delivers a signal to the non-professional antigen-presenting cell to activate the expression of co-stimulatory molecules. b. the T cell begins to express the α chain of the IL-2 receptor. c. the T cell differentiates into a TH1 cell. d. T-cell tolerance occurs as a result of anergy. e. the T cell is more heavily reliant on signals transmitted through CD4 or CD8 in order to become activated.
d
8-30 Which of the following statements regarding leprosy is false? a. It is caused by the bacterium Mycobacterium leprae. b. Disease progression is influenced depending on whether the immune response is polarized toward either a TH1 or TH2 response. c. The tuberculoid form of leprosy is associated with localized inflammation and granuloma formation. d. In lepromatous leprosy, the patient makes a TH2 response that clears the mycobacteria from the body. e. The less severe form of leprosy presents with high levels of IL-2 and IFN-γ produced by responding T cells.
d
8-32 An important way in which effector T cells differ from naive T cells is that _____. a. the cell-surface level of LFA-1 is lower on effector T cells b. L-selectin is upregulated during differentiation of effector T cells c. cellular proliferation occurs after effector T cells leave the secondary lymphoid tissues d. the provision of co-stimulatory signals is not required to induce a response by effector T cells e. effector T cells do not recirculate between lymph, blood, and secondary lymphoid tissues.
d
8-39 All of the following statements refer to regulatory T cells except ____. a. they produce anti-inflammatory cytokines b. they express elevated levels of CD25 c. they express FoxP3 d. they enhance the production of new effector T cells e. they suppress the function of existing T cells
d
8-44 Which of the following is not produced by T follicular helper (TFH) cells? a. CD4 b. IL-4 c. IFN-γ d. TNF-α e. IL-21
d
8-56 Binding of _____ to _____ induces T-cell proliferation and differentiation of activated T cells. a. CD4; MHC class II b. CD28; B7 c. LFA-1; ICAM-1 d. IL-2; the high-affinity IL-2 receptor e. IL-2; the low-affinity IL-2 receptor.
d
8-58 IL-4 is induced in a CD4 TH2 cell under the direction of the transcription factor _____. a. T-bet b. FoxP3 c. AP-1 d. GATA-3 e. NFAT.
d
8-17 All of the following are correctly matched except _____. a. TH1: T-bet b. Treg: FoxP3 c. IL-12: dendritic cells d. TH17: RORγT e. TH2: Bcl6.
e
8-22 The area of contact between membranes of a T cell and an antigen-presenting cell where a clustering of protein-protein interactions occur is called a(n) a. immunoreceptor tyrosine-based activation motif (ITAM) b. polarization c. cross-presentation center d. granuloma e. immunological synapse.
e
8-26 Which of the following is not a transcription factor, a component of a transcription factor, or an activator of transcription? a. Fos b. AP-1 c. NFκB d. NFAT e. JAKs f. FoxP3 g. GATA-3 h. T-bet i. STATs j. Jun k. Bcl6 l.RORγT
e
8-50 T cells failing to encounter specific antigen leave lymph nodes via the _________. a. germinal center b. bloodstream c. high endothelial venules d. afferent lymph e. efferent lymph.
e
8-60 Many cytokine receptors are associated with cytoplasmic protein kinases called _____, which become activated when the cytokine receptors bind to their respective cytokines. a. ZAP-70 b. STATs c. Lck d. ITAMS e. JAKs.
e
8-64 Which of the following characteristics permits activated CD8 T cells to destroy any cell type harboring viable and replicating pathogens such as viruses? a. The pathogen is located in extracellular spaces. b. CD8 T cells enable macrophages to kill intracellular pathogens. c. Pathogen-derived peptides bind MHC class I molecules in endocytic vesicles found ubiquitously in most cell types. d. MHC class II molecules are expressed ubiquitously by most nucleated cells. e. MHC class I molecules are expressed ubiquitously by most nucleated cells.
e
8-48 What are the roles of the following molecules in the signal transduction pathway leading from the T-cell receptor: (i) the CD3 complex; (ii) protein tyrosine kinase Lck; (iii) CD45; (iv) ZAP-70; (v) the ζ chain; (vi) inositol trisphosphate (IP3); (vii) calcineurin?
(i) The CD3 subunits γ, δ, and ε associated with the antigen-binding T-cell receptor help transmit the signal from the T-cell receptor-peptide-MHC interaction at the cell surface into the interior of the cell through immunoreceptor tyrosine-based activation motifs (ITAMs) present on their cytoplasmic tails. These are phosphorylated by associated protein tyrosine kinases, such as Fyn, when the antigen receptor is activated, and in turn activate further molecules of the signaling pathway. (ii) Lck associates with the tails of the CD4 and CD8 co-receptors. When these participate in binding to peptide:MHC complexes, Lck is activated and phosphorylates ZAP-70, a cytoplasmic protein tyrosine kinase. (iii) CD45 is a cell-surface protein phosphatase that helps activate Lck and other kinases by removing inhibitory phosphate groups from their tails. (iv) When ZAP-70 is phosphorylated, it binds to the phosphorylated ITAMs of (v) the ζ chain, which initiates the signal transduction cascade by activating phospholipase C-γ (PLC-γ) and guanine-exchange factors. (vi) IP3, which is produced by the action of PLC-γ on membrane inositol phospholipids, causes an increase in intracellular Ca2+ levels, which leads to the activation of the protein calcineurin. (vii) Calcineurin activates the transcription factor NFAT by removing an inhibitory phosphate group. Activated NFAT enters the nucleus, and together with the transcription factors NFκB and AP-1 will initiate the transcription of genes that lead to T-cell proliferation and differentiation.
8-49 Describe two distinct mechanisms by which naive CD8 T cells can be activated.
(i) Virus-infected dendritic cells provide adequate co-stimulation (via B7) and can activate CD8 T cells directly without the involvement of CD4 T cells. CD8 T cells receive signal 1 (MHC:T-cell receptor) and signal 2 (B7:CD28), synthesize IL-2 and the high-affinity IL-2 receptor, and proliferate and differentiate into cytotoxic T cells. (ii) In some cases, virus-infected dendritic cells cannot on their own fully activate naive CD8 T cells but the CD8 T cell begins to express IL-2 receptors. With the provision of help from effector CD4 T cells in the form of IL-2 secretion, these CD8 T cells are fully activated. For this to occur, simultaneous interaction with both the naive CD8 T cell and the effector CD4 T cell must occur.
8-63 The etiological agent responsible for leprosy is Mycobacterium leprae, which survives and replicates within the vesicular system of macrophages. Explain the difference between tuberculoid leprosy and lepromatous leprosy in the context of T-cell differentiation and effector function.
8-63 Effective immune responses against intravesicular pathogens living in macrophages are mediated by TH1 cells rather than TH2 cells. In tuberculoid leprosy, the predominant effector T cells produced after infection are TH1 cells. These are effective in containing the infection, although they do not clear it completely. The disease is chronic and progresses slowly, and the damage to skin and peripheral nerves is caused mainly by the inflammatory responses initiated by activated macrophages. In lepromatous leprosy, in contrast, the predominant T cells produced are TH2 cells. Humoral immunity is induced, which results in the production of antibodies that are ineffective against intracellular bacteria. As a result, M. leprae replicates unchecked, causing severe tissue destruction and eventually the death of the patient. Many factors influence the differentiation of CD4 T cells into TH1 or TH2 cells, including the cytokines produced by the antigen-presenting cells and leukocytes involved in the innate immune responses, the antigen concentration and peptide:MHC density, T-cell receptor affinity for peptide:MHC, and the cytokines produced by TH1 and TH2 cells themselves. If TH1 cells dominate an immune response, a cell-mediated immune response is favored. If TH2 cells dominate, a humoral immune response is favored.
8-46 Virus-infected cells attacked and killed by effector cytotoxic T cells are often surrounded by healthy tissue, which is spared from destruction. A. Explain the mechanism that ensures that cytotoxic T cells kill only the virus-infected cells (the target cells). B. What cytotoxins do cytotoxic T cells produce?
A. Cytotoxic T cells focus their killing machinery on target cells through a process called polarization. The cytoskeleton and the cytoplasmic vesicles containing lytic granules are oriented toward the area on the target cell where peptide:MHC class I complexes are engaging T-cell receptors. In the T cell, the microtubule-organizing center, Golgi apparatus, and lytic granules, which contain cytotoxins, align toward the target cells. The lytic granules then fuse with the cell membrane, releasing their contents into the small gap between the T cell and the target cell, resulting in the deposition of cytotoxins on the surface of the target cell. The cytotoxic T cell is not killed in this process and will continue to make cytotoxins for release onto other target cells, thereby killing numerous target cells in a localized area in succession. B. The cytotoxins include perforin, granzymes, and granulysin, molecules that induce apoptosis (programmed cell death) of the target cell.
8-15 A. Which cell-surface glycoprotein distinguishes professional antigen-presenting cells from other cells and is involved in the co-stimulation of T cells? B. What receptors can it bind on the T cell and what signal does it deliver in each case? C. Explain the consequence of antigen recognition by T cells in the absence of this glycoprotein on the antigen-presenting cell.
A. Expression of B7, a co-stimulator molecule, distinguishes professional antigen-presenting cells from other cells. B. When B7 binds to CD28, the B7 receptor expressed earliest on T cells, an activating signal is delivered and T cells undergo clonal expansion and differentiation. This interaction requires, of course, that the T-cell receptor and co-receptor are engaged specifically with a peptide:MHC molecule complex. The second B7 receptor, CTLA4, binds B7 with about 20-fold higher affinity than does CD28. An inhibitory signal is delivered to the T cell when B7 on the professional antigen-presenting cell binds to CTLA4. This mechanism serves to regulate T-cell proliferation and to suppress T-cell activation after an immune response. C. If they engage antigen in the absence of B7 expression and, hence, co-stimulation, T cells will become irreversibly non-responsive (anergic) instead of activated. This is one mechanism by which T-cell tolerance may be achieved.
8-10 A. Explain the functional differences between immature and mature dendritic cells. B. Discuss why you think these functional changes should occur.
A. Immature dendritic cells are very effective in the process of antigen capture, uptake, and processing. They have specialized pathways of antigen processing for extracellular antigens that can present these antigens on both MHC class I and class II molecules. They do not express co-stimulatory molecules. Immature dendritic cells migrate to nearby lymphoid tissue after antigen ingestion. Upon arrival in the lymphoid tissue, they differentiate into mature dendritic cells. These mature dendritic cells are now non-phagocytic and express the co-stimulatory molecule B7. B. Immature dendritic cells need to be phagocytic because they are located in sites susceptible to infection. Expression of B7 in non-lymphoid tissue is not required because this is not where T cells circulate and sample peptide:MHC complexes. Once outside the infected tissue, mature dendritic cells no longer need to phagocytose material. They do, however, need to express B7 molecules, because without co-stimulation, T cells do not receive the necessary activation signal for differentiation into effector T cells.
8-4 A. At which anatomical sites do naive T cells encounter antigen? B. In which sites specifically would a pathogen or its antigens end up, and how would they be transported to these sites, if they (i) entered the body through a small wound in the skin, (ii) entered the body from the gut, or (iii) got into the bloodstream? C. How do naive T cells arrive at these sites? D. Do all T cells leave these locations after priming, and if so, how?
A. Naive T cells encounter antigen, and start the primary immune response, in a secondary lymphoid tissue (for example lymph nodes, spleen, Peyer's patches, tonsils). B. (i) Lymph nodes. The pathogen, and dendritic cells that have ingested the pathogen, are carried to the nearest lymph node in the afferent lymph. (ii) Gut-associated lymphoid tissues (GALT) such as Peyer's patches. Pathogens enter GALT via specialized cells (M cells) in the gut epithelium. (iii) Spleen. Pathogens circulating in the blood enter the spleen directly from the blood vessels that feed it. C. Naive T cells are delivered to all secondary lymphoid organs from the blood. They can also pass from one lymph node to another via a lymphatic. D.After differentiation, CD8 effector cells and CD4 TH1, TH2, TH17, and regulatory T cells exit from the lymphoid tissue (via efferent lymph, which delivers them eventually into the blood) in search of infected tissues. Antigen-activated CD4 TFH cells remain in the lymphoid tissue where they provide help to antigen-specific B cells.
8-7 A. Which selectins, mucin-like vascular addressins, and integrins have a role in the circulation of T cells between the blood and lymphoid tissues? B. Describe in chronological order how T cells migrate across lymph node high endothelial venules (HEVs) from the blood by using these molecules.
A. T cells (and B cells) express L-selectin, which binds to sulfated carbohydrates of mucin-like vascular addressins in HEVs. Three types of mucin-like vascular addressin are involved: GlyCAM-1 and CD34 expressed on lymph-node HEVs, and MAdCAM-1 expressed on mucosal endothelium. B. Chemokines made by endothelium and bound to its extracellular matrix induce T cells to express LFA-1, an integrin. LFA-1 binds with high affinity to an intercellular adhesion molecule, ICAM-1, expressed on the endothelium. Finally, the T cell squeezes between the endothelium junctions, a process called diapedesis, and hence gains entry into the lymph node.
8-9 A. Identify three types of professional antigen-presenting cell. B. How are they distributed in secondary lymphoid tissue? C. Which kinds of antigen do they present efficiently to T cells?
A. The three types of professional antigen-presenting cells are dendritic cells, macrophages, and B cells. B. Dendritic cells are found in T-cell-rich areas of secondary lymphoid tissue; macrophages are distributed throughout the tissue; B cells are localized in lymphoid follicles. C. Dendritic cells present all types of antigen but present viral antigens particularly efficiently. Macrophages present bacterial antigens well because they bear generalized receptors that can bind and internalize many different bacteria. B cells present peptides of soluble protein antigens, such as protein toxins, that they have internalized via their antigen receptors.
8-3 Explain what feature of B cells makes them useful as professional antigen-presenting cells in an immune response.
B cells are armed with cell-surface immunoglobulin that binds with a very high degree of specificity to intact pathogen moieties. Once bound, the immunoglobulin:native antigen complex is internalized by receptor-mediated endocytosis, and the pathogen is degraded within endocytic vesicles. Pathogen-derived peptides from this degraded material bind to MHC class II molecules within the endocytic vesicles and are subsequently presented on the cell surface to CD4 T cells.
