Interactions of Phagocytes and Other Immunological Cells

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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