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[email protected] Questions for the Final: Slide presentation Immunity paper (survivin) Immunity paper (Gr. A induced apoptosis). Cell Mediated Cytotoxicity and Apoptosis. Cytotoxic T cells and granule exocytosis Trafficking of granules to the plasma membrane in CTL

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Elias haddad umontreal

[email protected]

Questions for the Final:

Slide presentation

Immunity paper (survivin)

Immunity paper (Gr. A induced apoptosis)


Elias haddad umontreal

Cell Mediated Cytotoxicity and Apoptosis

  • Cytotoxic T cells and granule exocytosis

  • Trafficking of granules to the plasma membrane in CTL

  • Entry of cytolytic molecules into target cells

  • Granule mediated apoptosis (Granzyme B and Granzyme A)

  • Discuss the Gr. A paper

  • 2. Discuss paper by Croft et al., (Survivin in memory T cell generation and maintenance)


Elias haddad umontreal

  • Why study CTL cytotoxicity?

  • In vitro Evidence:

  • MLR, Cr Release assay, killing virally infected cells and tumor cells.

  • In vivo Evidence:

  • Histological analysis: presence of CTL and its granules in pathological sites.

  • Adoptive transfer: Generating CTL specific for certain antigens and transferring them to naïve animals.

  • Knockout mice:Perforin is needed for the clearance of certain viral and bacterial infections.

  • Cancer: perforin deficient mice have shown increased occurrence of certain tumors.


Elias haddad umontreal

CTLs kill target by 2 different mechanisms:

  • Granule Exocytosis

  • Fas/FasL


Elias haddad umontreal

Mice with deficiencies or

mutations in CTL death pathways


Elias haddad umontreal

Cytotoxic Lymphocyte Granule Components

  • Perforin/Cytolysin

  • Granzymes

  • Granzyme A, Granzyme B, Granzymes C-H

  • Serglycin/Chondroitin sulfate proteoglycan

  • Granulysin

  • Lysosomal enzymes

  • Proteases, Cathepsins BHLC(W)

  • Cathepsins DE

  • Glycosidases, Other degradative enzymes

  • Chemokines

  • MIP1-a, MIP1-b, RANTES

  • Calreticulin

  • Granule membrane proteins

  • CTLA-4

  • LAMPs

  • Man-6-PR


Elias haddad umontreal

Granzymes: Subfamily of serine proteases found in the secretory granules of hematopoietic cells

Cytotoxic T lymphocyte granules contain:

1) Granzyme A, with “tryptase” specificity cleaving after arg or lys residues. Measured by the sensitive BLT esterase assay.

2) Granzyme B, with an unusual “aspase” specificity cleaving after asp residues. Can process and activate caspases 3,7,8,9&10.

3) Granzymes C-G, expressed at lower levels, with poorly defined “chymase” specificity. Not detectable in CTL in vivo.


Elias haddad umontreal

Variations on a theme of lysosomal secretion. Summary of the protein machinery identified in lysosomal secretion in spermatid (acrosomal granule, orange) , platelets, fibroblasts, CTL, melanocytes, and mast cells. Secretion of lysosomes (white) is required for secretion in some cell types and can involve movement along microtubules (black) in a plus or minus direction.


Elias haddad umontreal

Trafficking of cytolytic granules to the

plasma membrane in CTL

  • Natural mutations (Human & Mice)

  • Chediak-Higashi syndrome (lyst-function unknown)-beige mice

  • Griscelli syndrome (Rab27a- vesicle docking)-ashen mice

  • Familial haemophagocytic lymphohistiocytosis (FHL)

  • (pfp & Munc13-4 mutations

  • 4. Hermansky-Pudlak syndrome (Adaptor protein-3 (AP3).


Elias haddad umontreal

Protein secretion can utilize two export pathways

(Disrupted by Brefeldin A)

From: Molecular Biology of the Cell

00020


Elias haddad umontreal

Regulation of intracellular membrane vesicle fusion

Munc-18

Pfeffer, Nature Cell Biology 1:E17 (1999)


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