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1、BIOL 533,1,Interactions of Phagocytes and Other Immunological Cells,BIOL 533 Lecture 7,Medical Microbiology,BIOL 533,2,Production of Ab and Activation of Macrophages and Cytotoxic T Cells,T-Dependent T-Independent,BIOL 533,3,T-Dependent Activation,Extracellular pathogens Digested by macrophageAg com
2、plexed MHC class II (present only in macrophage and few other cell types) Stimulates helper T cells (TH2) to find B cells, recognize particular peptide fragmentAb Helper T cells (CD4+ cells; TH1) produces IFN and activates macrophage,BIOL 533,4,T-Dependent Activation,Intracellular pathogens Digested
3、 when released from dying host cell Peptide Ag presented on MHC class I Proliferation of cytotoxic T cells (CD8+),BIOL 533,6,T-Dependent Mechanism,Macrophage presents part of Ag and own class II MHC to T-helper cell (signal #1) Also makes IL1 6 (signal #2) IL1 6 stimulates T cell clone to divide and
4、 make IL2 4-6 IL1 also stimulates hypothalamus to raise body temperature, enhancing T cell action,BIOL 533,7,T-Dependent Mechanism,IL2 4-6 stimulate T-helper cells to multiply These T cells associate with B cells that have correct Ag MHC II complex and secrete B cell growth factors (BCGF) that cause
5、 B cells to multiply,BIOL 533,8,T-Dependent Mechanism,The number of B cells increase, T-helper cells produce other cytokines (BCDF) These cause some B cells to stop dividing, differentiating into plasma cells and produce Ab Also B cell recognizes its Ag through its surface IgM receptor (signal #1 fo
6、r B cell), subsequently triggered to proliferateplasma cellsAb,BIOL 533,9,T Cell Biology,MHC molecules Major Histocompatibility Complex Found on plasma membrane Class I found on most nucleated body cells Class II found only on leukocytes involved in immune response (macrophage, Ag-presenting cells,
7、B cells) Class I and II Ag processed differently,BIOL 533,10,T Cell Biology,Class I molecules bind to peptides found in cytosol (e.g., replicating viruses) Endogenous proteins are digested by natural processes Peptides from cytosolendoplasmic reticulum,BIOL 533,11,T Cell Biology,Within ER, class I M
8、HC heavy chain synthesized and associates with 2 microglobulin Dimer binds peptide plasma membrane If peptide is foreign, passing CD8+ T cell (cytotoxic) recognizes, releases cytokines, destroys cell,BIOL 533,12,T Cell Biology,Class II MHC bind to fragments arise from exogenous Ag Peptide recognized
9、 by CD4+ T-helper cells Do not directly kill cell cells enlarge and dividemore CD4+ cells Secrete cytokines (such as IL2) either directly inhibit pathogen or recruit other cells for immune response,BIOL 533,13,MHC Genetics,MHC gene complex located chromosome 6 ABCD co-dominant Individuals may have a
10、ny combination of 8 different MHC molecules One gene of each pair code for MHC,BIOL 533,14,MHC Genetics,Types of Genes Class IABC Class IID Class III Encode second component of complement (C2)classical pathway Factor Balternate pathway Two forms; 4th complement components (C4a C4b),BIOL 533,15,Regul
11、ator T Cells,T-helper CD4+ TH1: IL2, IFN, TNF; macrophage activation TH2: IL 4, 5, 10, 13; humoral immunity TH0: not much known T-suppressor,BIOL 533,16,Regulator T Cells,T-helper: two signals for stimulation by Ag Ag fragments presented to T cell by macrophage, dendritic, or activated B cell + MHC
12、class II; needed for recognition by T-cell receptor and CD4 protein on surface TH1 cell CD28 protein receptor on TH1 cells CD28 binds to CD80 on macrophage2nd signal; both go into cytoplasm of TH1 cell,BIOL 533,17,Regulator T Cells,Signal 1 activates tyrosine kinase Adds phosphate groups to tyrosine
13、 in proteins Enzyme phospholipase CI cleaves phosphatidyl inositol bisphosphate in T cell helper membrane Two cleavage products; two pathways First diacyl glycerol activates protein kinase C Protein kinase C moves into nucleus catalyzes formation protein complex AP1,BIOL 533,18,Regulator T Cells,Sec
14、ond, inositol triphosphate causes Ca channel to open; Ca+ ions rush in cytosol; activation of calmodulin, calcineurin, and nuclear factor of activated TH1,BIOL 533,19,Regulator T Cells,NF-ATnucleoplasm binds to AP-1 NF-AT/AP-1 (transcription factor) Transcription factor binds to DNA specific gene se
15、quence: IL2 m-RNA transcribed IL2m-RNAribosomes where IL2 protein produced,BIOL 533,20,Regulator T Cells,Signal 2 mediated CD28 receptor plus CD80 molecule activates another tyrosine kinaseformation transcription factor CD28RC; also stabilizes IL2 m-RNA; increases concentration of IL2 TH1 cells acti
16、vated by 2 signals secrete large amounts of IL2activates cytotoxic T cells,BIOL 533,21,Regulator T Cells,Signal 2 mediated, contd. Also secrete IFN which activates macrophages and enhances antimicrobial activity TH2 cells costimulated by Ag presentation and IL1, then release several cytokines that stimulate B cell proliferation and differentiation into Ab forming plasma cells,BIOL 533,22,Cytotoxic T Cells CD8+,Destroy target cells CD95 pathway (fas gene produces; apoptosis sequence) Perforin pa
