Chapter 9 - Janeway\'s Immunobiology PDF

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Chapter 9 T-cell Mediated Immunity Adaptive immune responses are initiated in the peripheral lymphoid organs: lymph nodes, spleen, peyer’s patches in the gut (MALT). Antigens are presented to mature circulating Tcells by dendritic cells in secondary lymphoid tissue: antigen encountering: activation into effector T-cells. Secondary lymphoid organs have T-cell zones and B-cell zones: white pulp. Each area of the white pulpis demarcated from the red pulp by marginal sinus. Follicular dendritic cells FCDs: have long processed that are in contact with B cells. They are not bone marrow derived leucocytes, and they aren’t phagocytic and they do not express MHC II molecules. FDC capture the antigen in the form of immune complexes: antigen-complement, antigen antibody. The complexes aren’t internalized but remain on the surface and presented to B cells. Interdigitating dendritic cells: bone marrow derived dendritic cells present in the T-cell zones. The development of secondary lymphoid organs is orchestrated by chemokines. Circulating T and B cells seed secondary lymphoid tissues from the blood by a common route, but are then directed into their respective compartments under the control of distinct chemokines that are produced by both stromal cells and bone marrow-derived cells resident in the T- and B-cell zones (such as FDC). The localization of T cells into T-cell zones involves two chemokines, CCL19 (secreted by dendritic cells) and CCL21 (secondary lymphoid chemokine, SLC). Both of these bind the receptor CCR7, which is expressed by T cells. Mice lacking CCR7 do not form normal T-cell zones and have impaired primary immune responses.

Like T-cells, B cells express CCR7, which directs them into lymph nodes across HEVs. They also express receptor CXCR5, they are attracted to the follicles by CXCL13 secreted by FDC. Naïve T-cells circulate from the blood stream into secondary lymphoid organs, via high endothelial venules (HEV). There it encounters many antigens represented by APCs. When a T-cell binds a peptide:MHC complex, it proliferates for several days, undergo clonal expansion and differentiation: giving rise to effector T-cells and memory T-cells with the same antigenic specificity. Effector T-cells then exit the lymph nodes through the efferent lymphatics, reenter

the blood stream and migrates to the site of infection. T-cells which doesn’t recognize a peptide:MHC complex exit the lymph nodes via efferent lymphatics and recirculate in the blood, till next time. The exception to this type of recirculation is the spleen: has no connection to the lymphatic vessels: exit and entry from the blood. Duration of this process ~5 days. Lymphocyte entry to lymphoid tissue: 4 stages: 1. Rolling along the endothelial surface: L-selectins (CD62L) expressed on Tlymphocytes bind to CD34 and GlyCAM-1 (addressins) expressed on HEV and/or MAdCAM-1 expressed on endothelial mucosae of MALT. Interaction between Lselectin and the vascular addressins is responsible for specific homing of naive T-cells to lymphoid organs. On its own, however, it doesn’t enable the cells to cross. 2. Activation of integrins: chemokines present at the luminal surface of the HEV (CCL21) activate integrins present of the T-cells to bind adhesion molecules. 3. Firm Adhesion: integrins such as LFA-1 binds ICAMs, VCAMs on the endothelial surface 4. Diapedesis across the endothelial: extravasation is promted by CCL21 secreted inside of the lumen by stromal cells and HEVs.

T-cells exist from a lymph node via cortical sinuses, which lead to medullary sinuses and hence into the efferent lymphatic vessels. sphingosine 1-phosphate (S1P) gradient. The level of sphingosine 1-phosphate (S1P) within lymphoid tissue is low compared with efferent lymph, thereby forming an S1P gradient. Naïve T-cells expressing the a S1P receptor go back to the circulation (T-cells not activated by an antigen). T cells activated by an antigen-expressing dendritic cell upregulate CD69, which causes a decrease in S1PR1 expression and retention in the T-cell zone. Effector T cells eventually reexpress S1PR1 as CD69 expression decreases, and thereby egress from the lymph node. Interdigitating dendritic cells: found mainly in the T-cell areas, in the cortex of a lymph node. • Macrophages are distributed throughout the node, but concentrated mainly in the marginal sinuses. • B-cells are found mainly in the follicles of the node. •

There are 2 classes of dendritic cells: 1. Conventional dendritic cell: are found under most surface epithelia, and in most solid organs, heart and kidneys. Prime naïve T-cells. 2. Plasmacytoid dendritic cell: less efficient in priming T-cells, express intracellular TLRs for sensing viral infection. Immature dendritic cells are associated with low levels of MHC molecules and B7 costimulatory molecules, so they’re not equipped to prime naïve T-cells. However, they’re active in phagocytosis. Routes of antigen processing and presentation by dendritic cells A. Delivery to MHC II molecules to prime CD4 T-cells 1. Receptor mediated phagocytosis: extracellular bacteria 2. Micropinocytosis: extracellular bacteria (capsulated, can’t bind the receptor), soluble antigens, viral particles. Major route for delivering M peptides to MHC II molecules. B. Delivery to MHC I molecules priming CD8 3. Viral infection of the cell, antigen processing and presentation. Major route for delivering peptides to MHC I molecules 4. Cross-presentation: extracellular antigens are taken inside for processing and presentation to CD8 cells. 5. Antigens can be also transmitted from one cell to another. This route is important because some viruses don’t infect all dendritic cells. Example: HSV infects the dendritic cells and can rapidly kill them. The antigens, however, can still be crosspresented by other dendritic cells which weren’t infected but they were activated through their TLRs. These cells uptake the dying dendritic debris and cross present this material. Langerhans cells: immature conventional cells which reside in the skin. They are actively phagocytic and contains large granules known as Birbeck granules. Langerhans pick up antigens from the site of infection, this trigger migration to lymph nodes. They then lose the ability to take up antigen but briefly increase the synthesis of MHC molecules. On arriving in the lymph nodes the also express co-stimulatory B7 molecules and large numbers of adhesion molecules = “become mature”, which enable them to interact with antigen specific T-cells. B7 positive dendritic cells can stimulate naïve T-cells.

A. Immature dendritic cells in peripheral tissues encounter pathogens and are activated by MAMPS. B. TLR signaling induces expression of CCR7 and enhances processing of pathogenderived antigens C. CCR7 directs migration of dendritic cells into lymphoid tissues an augments expression of co-stimulatory molecules and MHC molecules D. Mature dendritic cells in T-cell zone primes naïve T-cells. B-cells can use their surface immunoglobulin to present a specific antigen very efficiently to T-cells. Surface immunoglobulins bind antigens, especially if the antigen is present as soluble protein such as toxins. Co-stimulatory activity is induced in the B-cell by various microbial components: such induction results in expression of B7 molecule and antigen processing and presentation on MHC II molecules to T-cells. A. Antigen specific B-cell binds antigen B. Specific antigen is internalized by receptor mediated endocytosis, the vesicle then fuses with the vesicle containing MHC II molecule which binds peptides C. High density of specific antigen fragments presented Priming of naïve T cells by pathogen-activated dendritic cells Cell surface molecules of immunoglobulin super family are important in the interactions of lymphocytes with antigen-presenting cell. T-cell initially binds APC through low affinity LFA-1:ICAM interactions. LFA-1: ICAM1 and ICAM2, CD2: CD58. Subsequent binding of TCR to the peptide:MHC complex and binding of the co-receptor (CD4/CD8) signals LFA-1. Conformational change in LfA-1 increases affinity to ICAMs on APC and prolongs cell-cell contact. Antigen presenting cells deliver 3 kinds of signals for the clonal expansion and differentiation of naïve T-cells 1. Activation of naïve T-cell: TCR and co-receptor interaction with peptide:MHC complex. 2. Co-stimulatory signals that promote survival and expansion of the T-cells: B7 on the APC (member of immunoglobulin super family) bind CD28 on T-cell 3. T-cell differentiation into different T-cell subsets Naive T cells are found as small resting cells with condensed chromatin and scanty cytoplasm, and they synthesize little RNA or protein. On activation, they reenter the cell cycle and divide rapidly to produce large numbers of progeny that will differentiate into effector T cells. Their proliferation and differentiation are driven by INTERLEUKINE-2, which is produced by the activated cell itself. Antigen encounter by the TCR induces the synthesis of IL-2 and the alpha-chain of the IL-2 receptor

on the T-cell. The resting T-cell have only 2 (beta and gamma) of the 3 chains of the receptor. Binding of the alpha-chain increases affinity of the receptor to IL-2. Binding IL-2 to its receptor induces cell cycle, differentiation and proliferation. Proliferating T-cells differentiate into effector T-cells that do not require co-stimulation to act. After 4-5 days of rapid proliferation induced by IL-2, activated T-cell differentiate into effector T-cells that can synthesize all the molecules required for their specialized helper or cytotoxic functions. Once the cell has differentiated into effector cell, encounter with its specific antigen results in immune attack without the need for co-stimulation. Activation of T-cells changes the expression of several cell-surface receptors: L-selectin (CD62L) is lost, therefore T-cells cease to circulate back to the lymph nodes (homing). Instead they upregulate VLA-4 receptor after activation, which binds VCAM-1 expressed on the epithelial cells at the site of inflammation.

Cytotoxic T-cells can be activated in different ways to become cytotoxic effector cells Perhaps because the effector actions of these cells are so destructive, naïve CD8 T cells require more co-stimulatory activity to drive them to become activated effector cells than do naive CD4 T cells. CD8 activation requires help from the CD4 effector T-cell. CD8 T-cells may become activated only in the presence of CD4 T-cells interacting with the same antigen presenting cells. CD4 cells produce abundant IL-2 which helps drive T-cell proliferation. This activates the CD8 cell to make its own IL-2.

CD4 T-cells differentiate into several subsets of functionally different effector cells. In contrast with CD8 T-cells, CD4 T cells differentiate into several subsets of effector T-cells with a variety of different functions: TH1, TH2, TH17, regulatory T-cells, and T follicular helper cell TFH: provides help to B-cells in the lymphoid follicle. The subsets are defined on the basis of different cytokines they secret. 1. TH1: help eradicate infections by microbes that can replicate within the macrophage. Example: bacteria that can set up intravesicular infections in macrophages, such as mycobacteria that cause tuberculosis and leprosy, viruses and protozoans. 3. If a TH1 cell recognizes bacterial antigens displayed on the surface of an infected macrophage, it will activate the macrophage further through the release of IFN-γ, which enhances the macrophage’s microbicidal activity to kill ingested bacteria. Type 1 responses also promote B-cell class switching that favors production of opsonizing IgG antibodies. 2. TH2: help control infections by parasites: Helminths, through promoting responses by eosinophils, mast cells and IgE antibody. 3. TH17: helps protect against extracellular bacteria and and fungi through stimulating the neutrophils response which elps clear such pathogens. TH1, TH2 and TH17 can function outside the lymphoid tissues at site of infection to activate macrophages or aid in recruiting cells such as eosinophils and neutrophils. Another crucial function of CD4 T-cells is in providing help to B-cells for antibody production. TFH is the CD4 subset which provides help to B-cells for antibody production in the lymphoid

vesicles. TH1 and TH2 cells also influence the B-cells to produce antibody, by determining the antibody isotype to be produced. Regulatory T-cells: suppress T-cell responses. Involved in limiting the T-cell response and preventing autoimmune diseases. 2 main groups: 1. Natural regulatory T-cells: becomes committed to a regulatory fate while still in the thymus 2. Induced regulatory cells: differentiate from naïve CD4 T-cell Specific cytokines trigger CD4 T-cell differentiation: signals provided by APC cells priming the naïve T-cell in the lymph node.

CD4 T-cell subsets can cross-regulate each other’s differentiation through the cytokines they produce:

Example: mouse model infected with Leishmania major which requires a TH1 response and activation of macrophages for clearance. However, the CD4 T cells fail to develop into TH1 cells, instead they become TH2, which are unable to activate the macrophages to inhibit the growth of the parasite. This is due to production of IL-4 by a memory cell (something related to the mice). The IL-4 inhibits CD4 differentiation into TH1. If IL-4 was blocked by anti-IL-4 the infection can be cured. Interactions of T-cells with their targets initially involve non-specific adhesion molecules. A. The initial interaction of CD8 cell with target is made by non-specific adhesion molecules: ICAM1 :LFA-1 B. If no antigen specific interaction: TCR :peptide:MHC complex: cell separate A. Antigen specific interactions: stable binding and release of effector molecules: infected cell apoptosis and release of CD8 cell. Immunological synapse: synapse between APC and T-cell through adhesion molecules. Cytotoxic granules (found only in CD8 T-cells and NK cells) are released at the site of cell contact=apoptosis. Different subsets of T-effector cells produce different effector molecules 1. Cytotoxic effector molecules: perforin, granzymes IFN-gamma, TNF-alpha 2. TH1: macrophage activating effector molecule: IFN-gamma, TNF-alpha 3. TH2: barrier immunity activating effector molecules: IL-4 4. TH17: neutrophil recruitment: IL-17 5. Treg: suppressive cytokines: IL-10, TGF-ß Apoptosis: self-destruction from within: DNA fragmentation by nucleases. Before destruction of the nucleus and DNA, the cellular organelles are degraded by large vacuoles. Cells shrivel up without lysing. Apoptosis induced by CD8 cells: A. By cytotoxic granules Perforin: facilitates the delivery of the granzyme into the cytosol Granzyme: serine protease which activates apoptosis 1. Engagement of TCR by peptide:MHC complex causes directed release of perforin and granzymes 2. Granzyme is delivered into the cytosol of the infected cell and targets BID and procaspase 3 3. Truncated BID disrupts mitochondrial membrane, and activated caspase 3 cleaves ICAD, releasing caspase activated DNase (CAD). 4. Release of cytochrome c into cytosol activates apoptosis, and CAD induces DNA fragmentation. B. Mitochondrial release of cytochrome c

The intrinsic pathway of apoptosis is mediated by the release of cytochrome C from mitochondria....