Interactions of Phagocytes and Other Immunological Cells

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Interactions of Phagocytes and Other
Immunological Cells
Medical Microbiology

• BIOL 533
• Lecture 7

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Production of Ab and Activation of Macrophages
and Cytotoxic T Cells

• T-Dependent
• T-Independent

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T-Dependent Activation

• Extracellular pathogens
• Digested by macrophageAg 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 fragment?Ab
• Helper T cells (CD4 cells TH1) produces IFN?
  and activates macrophage

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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)

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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)

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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

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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

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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 proliferate?plasma cells?Ab

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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

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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 cytosol?endoplasmic reticulum

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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

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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 divide?more CD4 cells
• Secrete cytokines (such as IL2) either directly
  inhibit pathogen or recruit other cells for
  immune response

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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

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MHC Genetics

• Types of Genes
• Class I ABC
• Class II D
• Class III
• Encode second component of complement
  (C2)classical pathway
• Factor Balternate pathway
• Two forms 4th complement components (C4a C4b)

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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

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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 macrophage?2nd signal both
  go into cytoplasm of TH1 cell

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Regulator T Cells

• Signal 1 activates tyrosine kinase
• Adds phosphate groups to tyrosine in proteins
• Enzyme phospholipase C?I 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

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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

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Regulator T Cells

• NF-AT?nucleoplasm binds to AP-1 NF-AT/AP-1
  (transcription factor)
• Transcription factor binds to DNA specific gene
  sequence IL2 m-RNA transcribed
• IL2m-RNA?ribosomes where IL2 protein produced

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Regulator T Cells

• Signal 2 mediated
• CD28 receptor plus CD80 molecule activates
  another tyrosine kinase?formation transcription
  factor CD28RC also stabilizes IL2 m-RNA
  increases concentration of IL2
• TH1 cells activated by 2 signals secrete large
  amounts of IL2?activates cytotoxic T cells

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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

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Cytotoxic T Cells CD8

• Destroy target cells
• CD95 pathway (fas gene produces apoptosis
  sequence)
• Perforin pathway?direct cytolysis secretion of
  perforin and granzyme proteins

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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
  proteins?cellular suicide sequence

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Cytotoxic T Cells CD8

• Perforin pathway
• Ca2 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

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Lecture 7

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