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At which anatomical sites do naive T cells encounter antigen?
- Naive T cells encounter antigen and start the primary immune response in secondary lymphoid tissue.
- lymph nodes
- payer's patch
- tonsils, etc.
Naive T cells are delivered to all secondary lymphoid organs from the blood where they are primed. What happens after that?
After activation by antigen only CD8 and TH1 cells exit the lymphoid tissue in search of infected tissues. Antigen-activated Th2 cells remain in the lymphoid tissue, where they provide help to antigen-specific B cells.
Why do T cells take several days to mount a primary response?
First, antigen needs to be transported to a nearby secondary lymphoid tissue, processed, and presented by APCs to naive cytotoxic T cells or helper T cells so as to activate them. Second, the # of T cells specific for a given pathogen will be only around 1 in 10,000 to 1 in 100,000 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 tissues 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.
Which selectins, mucin-like vascular addressins, and integrins have a role in the circulation of T cells between the blood and lymphoid tissues?
T cells (and B cells) express L-selectin, which binds to sulfated carbohydrates of mucin-like vascular addressins in HEVs .
Why are dendritic cells more efficient than macrophages at stimulating naive T-cells?
Dendritic cells are migratory and transport antigen to neighboring secondary lymphoid tissue.
Migration of B cells into secondary lymphatic tissues
- Enter HEV and follow a chemokine gradient into spleen and contact BAFF
- Before BAFF crosslink w/ B receptor leads to death
- After BAFF crosslink w/ B receptor leads to maturation
Naive B cells that have just left the marrow have what 2 Ig's?
IgM or IgD
T cell dependent B cell activation (interaction occurs at lymphoid organs)
- Antigen stimulates B cell Ig
- Ig cross-linking causes transcription signal cascade
- Antigen concentrated on naive B cells (CR2 -- C3d)
- B-cells express B7(makes them receptive to T-cell help)
- T cells bind MHC class II w/ CD4 and B7 w/ CD28 B cell expresses CD40T cell binds CD40 with CD40 ligand (2nd signal req. for T cell help)
- T cell expresses cytokines
- B cell activation
T cell cytokine influence
- Proliferation/differentiation: become antibody secreting cells (plasma end stage cell or memory cell)
- Isotype switching
- Affinity maturation: B cells migrate to lymph nodes/spleen and undergo somatic mutations to Ig chains -- B cells that end up losing affinity are eliminated.
Descrive in chronological order how T-cells migrate across lymph node HEVs from the blood.
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.
a) Which cell-surface glycoprotein on B-cells distinguishes professional APC's from other cells and is involved in the co-stimulation of T-cells?
b) What receptor can it bind to on T-cells and what signal does it deliverin each case?
b) B7 binds CD28, this signals the T-cells to undergo clonal expansion and differentiation. This interaction requires that the T-cell receptor and CD4 co-receptor are engaged specifically with a peptide:MHC class II complex. The second B7 receptor, CTLA-4 binds B7 about 20x tighter than CD28 (CTLA-4 is not expressed as early as CD28). An inhibitory signal is delivered to the T cell when B7 on the APC binds to CTLA-4. This mechanism serves to regulate T-cell proliferation and to suppress T-cell activation after an immune response.
Explain the consequences of antigen recognition by T-cells binding to B-cells that are not expressing B7.
If they engage antigen in the absence of B7 expression T cells will become irreversibly non-responsive (anergic) instead of activated. This is one mechanism by which T-cell tolerance may be achieved.
An adjuvant enhances the effectiveness of vaccines by inducing the expression of ______ on ________.
a) co-stimulatory molecules : dendritic cells
b) CD28 : macrophages
c) MHC class II : T-cells
d) TCR : T-cells
e) immunoreceptor tyrosine based activation motifs : dendritic cells
Name the 3 classes of effector T cells, how they recognize antigen and their corresponding effector functions.
- Cytotoxic T-cells: Recognize antigen on the surface of a cell that is presenting antigen bound to MHC class I. CD8s respond by killing these target cells by inducing the apoptotic pathway.
- TH1: recognize antigen bound to MHC class II molecules on the surface of an APC cell such as a macrophage. TH1 cells respond by activating the macrophage to destroy intravesicular bacteria and increase the phagocytosis of extracellular bacteria it has taken up.
- TH2: recognize antigen bound to MHC class II on the surface of B-cells. TH2s respond by secreting cytokines that activate B-cells to differentiate into antibody-producing plasma cells.
How do CD8 T-cells ensure that the toxins they release only target virus-infected cells?
Polarization: The cytoplamsic vesicles containing lytic granules are oriented toward the area on the target cell where the MHC Class I:peptide 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 cll 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 tother target cells, thereby killing numerous target cells in ta localized are in succession.
What cytotoxins do cytotoxic T-cells produce?
perforin, granzymes and granulysin, molecules that induce apoptosis of the target cell.
Which of the following are features of regulatory T cells?
a) Tregs express CD8 and control effector cells by inducing apoptosis.
b) Tregs express high levels of CD25 (IL-2 receptor alpha chain) and secrete pro-inflammatory cytokines such as IFN-gamma.
c) Physical association between Treg and its target cells is mandatory for Treg function.
d) By interacting with dendritic cells in secondary lymphoid tissue, Tregs prevent the interaction and activation of naive T cells.
e) Tregs secrete TGF-beta and suppress effector T-cell function.
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
v) the delta chain
- i) CD3 transduce the signal from the T-cell receptor-peptide-MHC interaction at the cell surface into the interior of the cell through ITAMs present on their cytoplasmic tails. This initiates a phosphorylation cascade 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 kinase.
- iii) CD45 is a cell-surface protein phosphatase that helps activate Lck and other kinases by removing inhibitory phosphotase groups from their tails.
- iv) When ZAP-70 is phosphorylated it binds ot the phosphorylated ITAMs of...
- v) the delta chain, which initiates the signal transduction cascade by activating phospholiapse C-gamma and guanine-exchange factors.
- vi) IP3 which is produced by the action of PLC-gamma on membrane inositol phospholipids, causes an increase in intracellular Ca 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 NFkB and AP-1 will initiate the transcription of genes that lead to T-cell proliferation and differentiation.
Which type of infection would lead to the formation of a granuloma and how is this beneficial to the host?
- Chronic infections resistant to the killing mechanisms of macrophages can lead to granulomas, for example in TB caused by mycobacterium tuberculosis growing inside intracellular vesicles.
- Granulomas are surrounded by CD4 T-cells which cut off the infection from the blood supply, and the cells in the ore of the granuloma will die from oxygen deprivation and toxic products of the macrophages. In TB dead tissue is referred to as caseation necrosis because it has a cheesy consistency. If the infection were not localized in this fashion, it could disseminate systemically to other anatomical locations.
Why does suppressing the transcription of the genes that are turned on by the signaling pathway that is activated by the cytokine IL-2 and alpha chain if the IL-2 receptor lead to immunosuppression? (helpful with translplants-- mechanism of cyclosporin A)
In an immune response, the binding of IL-2 to a high affinity IL-2 receptor composed of alpha, beta, and gamma chains drives the proliferation and differentiation of T-cells that occurs after they have encountered their specific antigen. The alpha chain is req. to form a complex with the preexisting beta and gamma chain to make the hgih-affinity receptor. Suppressing the alpha chain will prevent the formation of the high-affinity receptor and prevent clonal expansion of the T-cell.
What is the role of Fas (CD95)?
The interaction of Fas and Fas ligand is an important mechanism for eliminating lymphocytes when an infection has been terminated and during lymphocyte development. In the absence of functional Fas the size of the lymphocyte pool can no longer be regulated, and removal of autoimmune cells is ineffective. Secondary lymphoid tissue such as teh spleen and lymph nodes remain enlarged even in teh avsence of infection, and autoimmune responses are common -- both these conditions are seen in ALPS (autoimmune lymphoproliferative syndrome).
Polyvalent antigen B cell activation
- Natural antibodies
- Receptors can cross-link w/out ping pong match
- Stimulated by polysaccharides, nucleic acids, glycolipids
- IgM, poor response, no affinity maturation, no memory
- LPS binding TLR4, bacterial DNA => the 2nd signal req. for NFkB activation (similar to CD40 co-receptor in T-cell dependent activation)
Cross-linking of Ig by antigen is essential but not always sufficient to initiate the signal cascade for B cell activation. Stimulation of additional receptors is also necessary for the full activation and differentiation of naive B cells. Describe these receptors and their ligands, and outline how they help activate the B cell.
The B-cell co-receptor, made up of CD21, CD19 and CD81 (TAPA-1) cooperates with the BCR in B cell activation and increases the sensitivity of the B cell to antigen 1000-10000x. This becomes important when antigen concentrations are low. CD21 binds C3d, when the coreceptor and BCR are both ligated to antigen and C3d, Lyn and the cytoplasmic tail of CD19 come close together, leading to phosphorylation of CD19, which initiates activation leading to activation of the B cell.
Explain the difference between thymus dependent and thymus independent antigens.
- Thymus dependent: only induce generation of antibodies by B cells when T cell help is available (they induce memory as well as affinity maturation after somatic hypermutation). (peptide epitope)
- Thymus independent: induce antibodies even in the absence of T cell help. They do not induce isotype switching or somatic hypermutation, and no memory is produced. (LPS or Bacteria DNA)
T or F
a) Plasma cells produce secreted antibody, proliferate and undergo somatic hypermutation to produce antibodies with a higher affinity for antigen.
b) An immunodeficiency called hyper IgM syndrome is characterized by lack of CD40 ligand expression on T cells.
c) Antibody-dependent cell-mediated cytotoxicity (ADCC) is mediated by NK cells, which use their Fc receptors to bind to antibody-coated target cells, which they kill through inducing apoptosis.
d) TI-2 polysaccharide antigens are commonly used in vaccines administered to infants because they stimulate strong antibody responses.
- a) FALSE, B plasma cell is terminally differentiated B cell that is not dividing and cannot change its antibody specificity. Somatic hypermutation occurs before B-cells differentiate into plasma cells.
- b) TRUE
- c) TRUE
- d) FALSE, TI-2 polysaccharides activate only mature B cells, which are not fully acquired till age 5.
Why is CD40 ligand expression on T cell important?
CD40 ligand binds to CD40 on B cells, signaling B cells to activate NFkB, a transcription factor that upregulates the expression of ICAM-1, an adhesion molecule, on the surface of B cells.
Which of the following is a characteristic of follicular dendritic cells in the primary follicles of secondary lymphoid tissues?
a) they are bone marrow derived hematopoietic cells.
b) they provide a stable depository of intact antigens able to bind to BCRs.
c) they internalize immune complexes through CR2 receptor cross-linking.
d) they bear bundles of immune complexes called iccosomes that are passed on to antigen-specific B cells.
e) they produce cytokines that induce B cells to proliferate and become centroblasts.
What is the main effector function of the IgM antibody?
complement activation (it can also neutralize pathogens and toxins)
IgM is the first antibody to be produced by the plasma cells during a primary antibody response and is secreted as a pentamer that circulates in the blood. Because of the large size of pentameric IgM, it does not penetrate effectively into infected tissues and is most effective against pathogens in the bloodstream.
Augments production of IgA
Describe the course of events that results in the swollen lymph nodes characteristic of many infections.
B-cells that have bound specific antigen and encountered their cognate T-cells in the lymph nods are activated and start to proliferate. These activated B-cells move into primary follicles. The primary follicle enlarges and morphologically changes into a germinal center. The activated B-cells undergo somatic hypermutation while dividing in the germinal center, producing activated B-cells with mutated surface immunoglobulin. Only cells that take up antigen efficiently are present it to helper T cells will be selected to differentiate into plasma cells or memory cells. Antigen will be encountered at the surface of follicular dendritic cells as an immune complex. If B cells do not encounter their specific antigen they will undergo apoptosis and be ingested and cleared by macrophages. This takes about 7 days after an infection begins, and the increase in cell numbers accounts for the swollen lymph nodes.
Explain what passive transfer is and how it occurs via placental transfer and through breast milk.
- Passive transfer of immunity refers to the process of transferring preformed immunity from an immune subject to a nonimmune subject. This can be achieved by transferring whole serum purified antibody, monoclonal antibody, or intact effector or memory lymphocytes.
- IgG antibodies are transported transplacentally to provide passive protection in the bloodstream and extracellular spaces of tissues until the baby can begin making its own antibodies. IgA is transferred into the infant's GI tract in breast milk and protects the GI epithelia from colonization and invasion by ingested microorganisms.
Fc receptor-dependent phagocyte responses: complement activation; neonatal immunity (placental transfer)
Immunity against helminths
Mast cell degranulation (immediate hypersensitivity)
Mucosal immunity (transported through epithelia)
Antigen presenting cells (other than macrophages and B-cells)
Involved in the initiation of immunity (stimulate clonal expansion of naive T-cells)
Bone marrow derived of myeloid lineage
Reside in all tissues or solid organ
While they are immature they reside in the tissues sampling the environment (mostly phagcoytic)
When they receive a signal from a toll-like receptor or inflammatory cytokines they mature.
As mature cells the upregulate cytokine production and B7, ICAM and IL-12 (molecules involved in T-cell activation). They then migrate to lymphatics to present antigens and direct effector cells to the site of infection.
Priming of naive T-cells is done by ________ cells.
When do naive T-cells encounter antigen?
during their recirculation through secondary lymphoid organs.
- TCR complex and coreceptors clustered due to antigen recognition =>
- Lck phosphorylates ITAM =>
- ZAP-70 is activated and phosphorylates multiple substrates =>
- multiple signaling pathways are activated => IL-2 production.
IL-2 -- T-cell activation and proliferation
- IL-2 stimulates growth of T-cells (IL-4 also involved)
- Clonal expansion: inflammation, memory T-cells, T-cell mediated cytolysis, macrophage activation
- Accessory proteins (non-polymorphic, increase adhesion): LFA1(Tcell):ICAM-1(APC)=adhesion, CD28(Tcell):B7(APC)=important for signaling and T-cell activation.
TH1: drives the antibacterial, inflammatory response
- TH1 differentiation occurs in the presence of IL-12, which turns on STAT4 (IL-12 comes from activated macrophages and dendritic cells)
- TH1 cells act as effector cells w/ memory function
- IFN-gamma (major product): major isotype switching cytokine, activates complement, IgG1, leading to antibody production.
- LTalpha: lymph node organization
TH2: induces allergic response
- TH2 differentiation occurs in the presence of IL-4, which turns on STAT6.
- IL-4: induces IgE for allergic response (mast cell degranulation, eosinophil activation, neutralizing IgG antibodies, basophils), also suppresses macrophages.
- TGF-beta and IL-5 induce IgA, anti-inflammatory
Delayed type hypersensitivity TH17
- TH17: another subset of polarized T-cells (occurs in the presence of IL-6 an TFG-beta)
- Produces IL-17 in the presence of IL-23, which induces inflammatory cytokines (IL-6, IL-8) for neutrophil chemotaxis.
- IL-17 is made by CD4 cells and by CD8 and NKT cells.
- Job's syndrome: defect in STAT3 => not able to make IL17 and TH17 subset of cells
- IL17 deficiency is characterized by delayed neutrophil recruitment.
T Regulatory Cells
- Function: suppress autroreactive lymphocytes and immune reactions by down regulating effector T-cells (activated through TCR binding MHC:antigen complex; once activated Tregs suppress everyone, independent of antigen being expressed; immuno suppressive cytokines involved: IL-10, TGF-beta)
- CD25: key component of IL-2 receptor (alpha-chain) (makes T cells 100 times more sensitive to IL-2)
- FoxP3: defines Tregs -- blocks Tregs from ever becoming effector T-cells. Targets: CD25, Tnfrsf18, GITR, CTLA-4. (CTLA-4 also binds B7, but down regulates the signaling instead of upregulating like CD28 would)
- Natural/dedicated Tregs suppress autoimmunity (help control autoreactive T-cells)
Explain the immunological synapse
- Protein-protein interactions in the area of contact between a T-cell and an APC form an ordered structure called an immunological synapse.
- The area of contact is divided into the c-SMAC (central-supramolecular activation complex) and the p-SMAC (peripheral-supramolecular activation complex), in which different sets of T-cell proteins are segregated.
signaling receptors on the c-SMAC
Adhesion receptors on the p-SMAC
How does a CTL kill?
- Release granzymes (that enter the cell through holes made by perforin), which release proteases that activate the apoptotic pathway.
- FAS-L: release by NK cells and induces apoptosis
- CTL targets specific cells via cell to cell contact.
What is IPEX?
- Immune dysregulation polyendocrinopathy enteropathy X-linked
- (X-linked immunodeficiency syndrome associated w/ autoimmune dz in multiple endocrine organs)
- Hyperactivation of CD4 T-cells
- Overproduction of pro-inflammatory cytokines
- Gene defect in FoxP3 (FoxP3 encodes scurfin)
Suppressive functions of T-regs
- Stimulation via the TCR is req. for CD25+ CD4 T-reg cells to exert suppression (implies that natural CD25-- CD4 T-regs should recognize self antigens and must be stimulated to control self reactive T cells)
- CD25+ CD4 T-reg mediated suppression is highly sensitive to antigen stimulation; only very low Ag concentrations are needed to stimulate proliferation in T-regs (10-100 fold lower than req. for stimulating normal CD4 T cells).
- Suppression is NOT antigen specific: Bystander suppression
- Adaptive T-reg are generated during an infection to down-modulate effector T cell functions.
a) Decrease in Treg function can result in:
b) Increase in Treg function can result in:
a) autoimmune dz, allergy, microbial infection, tumor immunity
b) organ transplantation, feto-maternal tolerance.