interactions of phagocytes and other immunological cells
TRANSCRIPT
BIOL 533 1 Lecture 7
Interactions of Phagocytes and Other Immunological Cells
BIOL 533Lecture 7
Medical Microbiology
BIOL 533 2 Lecture 7
Production of Ab and Activation of Macrophages and Cytotoxic T Cells
• T-Dependent
• T-Independent
BIOL 533 3 Lecture 7
T-Dependent Activation
• Extracellular pathogens– Digested by macrophage—Ag complexed
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 Lecture 7
T-Dependent Activation
• Intracellular pathogens– Digested when released from dying host
cell– Peptide Ag presented on MHC class I– Proliferation of cytotoxic T cells (CD8+)
BIOL 533 5 Lecture 7
Processing CHO and Lipid Ag
• LPS interacts directly with B cells (independent of T cells)
• CHO Ag largely independent of T cells, but some involvement (production of cytokines; necessary for maximal B cell activity)
BIOL 533 6 Lecture 7
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
make IL2 4-6– IL1 also stimulates hypothalamus to raise
body temperature, enhancing T cell action
BIOL 533 7 Lecture 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 B cells to multiply
BIOL 533 8 Lecture 7
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 for B cell), subsequently triggered to proliferateplasma cellsAb
BIOL 533 9 Lecture 7
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, B cells)
– Class I and II Ag processed differently
BIOL 533 10 Lecture 7
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 Lecture 7
T Cell Biology
• Within ER, class I MHC 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 Lecture 7
T Cell Biology
• Class II MHC bind to fragments arise from exogenous Ag
• Peptide recognized 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 Lecture 7
MHC Genetics
• MHC gene complex located chromosome 6
• ABCD co-dominant
• Individuals may have any combination of 8 different MHC molecules
• One gene of each pair code for MHC
BIOL 533 14 Lecture 7
MHC Genetics
• Types of Genes– Class I ABC– Class II D– Class III
• Encode second component of complement (C2)—classical pathway
• Factor B—alternate pathway• Two forms; 4th complement components
(C4a C4b)
BIOL 533 15 Lecture 7
Regulator 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 Lecture 7
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 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 Lecture 7
Regulator T Cells
• Signal 1 activates tyrosine kinase– Adds phosphate groups to tyrosine 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 Lecture 7
Regulator T Cells
– Second, 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 Lecture 7
Regulator T Cells
• NF-ATnucleoplasm binds to AP-1 NF-AT/AP-1 (transcription factor)
• Transcription factor binds to DNA specific gene sequence: IL2 m-RNA transcribed
• IL2m-RNAribosomes where IL2 protein produced
BIOL 533 20 Lecture 7
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 activated by 2 signals secrete large amounts of IL2activates cytotoxic T cells
BIOL 533 21 Lecture 7
Regulator T Cells
• Signal 2 mediated, cont’d.– 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 Lecture 7
Cytotoxic T Cells CD8+
• Destroy target cells– CD95 pathway (fas gene produces;
apoptosis sequence)– Perforin pathwaydirect cytolysis;
secretion of perforin and granzyme proteins
BIOL 533 23 Lecture 7
Cytotoxic T Cells CD8+
• CD95 Pathway– CD95 transmembrane fas protein
receptor found in many eukaryotic cells– CD95 coded fas gene; member of TNF
family of genes– Fas ligand binds
• CD95/CD95L complex activates several cytosolic proteinscellular suicide sequence
BIOL 533 24 Lecture 7
Cytotoxic T Cells CD8+
• Perforin pathway– Ca+2 dependent sequence
• Microtubule assembly• Movement of cytoplasmic granules• Reorientation of Golgi apparatus• Movement of microtubule organizing center
– T cell secretes pore-forming protein perforin– T cell secretes granzymes (proteolytic
enzymes further damage it), cause cytosis
BIOL 533 25 Lecture 7
Lecture 7
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