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Chapter 14 Cell-Mediated Effector Responses

Chapter 14 Cell-Mediated Effector Responses. Cell-mediated immunity: Detect and eliminate cells that harbor intracellular pathogens. Ag-specific cells – CD4 + T cells, CD8 + T cells Ag-nonspecific cells – NK cells macrophages

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Chapter 14 Cell-Mediated Effector Responses

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  1. Chapter 14 Cell-Mediated Effector Responses

  2. Cell-mediated immunity: Detect and eliminate cells that harbor intracellular pathogens. Ag-specific cells – CD4+ T cells, CD8+ T cells Ag-nonspecific cells – NK cells macrophages neutrophils eosinophils

  3. Cytotoxic T Cells

  4. Two major categories of cell-mediated immune responses: • Effector cells that have direct cytotoxic activity. • Effector cells that mediate delayed-type • hypersensitivity (DTH) reactions

  5. Three types of effector T cells: 1. CD4+ TH1cells 2. CD4+ TH2 cells 3. CD8+ CTLs Characteristics: - less stringent activation requirements - increased expression of cell-adhesion molecules - production of both membrane-bound and soluble effector molecules

  6. The CD45RO isoform associates with the TCR complex and • CD4/CD8 much better than does the CD45RA isoform. • - CD2 LFA-3, LFA-1 ICAMs

  7. - The FasL, perforins, and granzymes mediate target cell destruction by the CTLs. • - Membrane-bound TNFb and soluble IFNg and GM-CSF promote macrophage • activation by the TH1 cell. • The membrane-bound CD40L and soluble IL-4, IL-5, IL-6, and IL-10 play a role • in B cell activation by the TH2 cell.

  8. Generation of Effector CTLs B7 CD28

  9. Tumor-Cell Destruction by a CTL CTL tumor cell

  10. CTL-Mediated Killing of Target Cells perforin monomers & granzyme proteases

  11. Cell-Mediated Pore Formation in Target-Cell Membrane fusion release iCa++ insertion

  12. Perforin Pore on a Red Blood Cell • Perforin exhibits sequence • homology with C9, and the • pores formed by perforin are • similar to those observed in • complement-mediated lysis. • The perforin pores facilitate • entry of granzyme proteases • into the cell. • Granzymes activate an apop- • totic pathway within the cell.

  13. CTL Can Use Fas to Lyze a Target Cell

  14. CTL-mediated Killing Depends on Perforin, Fas, or A Combination of the Two

  15. CTL-Mediated Apoptotic Pathways Caspase: cysteine, aspartate protease

  16. Natural Killer Cells

  17. Natural Killer (NK) Cells: • 5 - 10% of the recirculating lymphocyte population • No immunization is required. No memory • a population of large granular lymphocytes • constitutively cytotoxic, always having large granules • - involved in the defense against viruses and tumors • Activity is stimulated by IFNa, IFNb, and IL-12. • express CD16 (FcgRIII) • do not express TCR/CD3 • Recognition is not MHC-restricted. • normal in RAG-1, RAG-2, and SCID mice • Cytotoxicity depends on perforin and granzymes.

  18. Time Course of Viral Infection

  19. NK-Cell Receptors Activation Receptors: NKR-P1 (a C-type lectin recognizing carbohydrates) Inhibitory Receptors: CD94/NKG2 (recognizing HLA-E with an HLA peptide) KIR (> 50 members; specific for one or a limited number of polymorphic products of particular HLA loci)

  20. Opposing-signals Model of NK Activity KIR: killing inhibitory receptor AR: activation receptor

  21. Ab-Dependent Cell-Mediated Cytotoxicity (ADCC)

  22. Experimental Assessment of Cell-mediated Cytotoxicity Mixed Lymphocyte Reaction (MLR) Cell-mediated Lympholysis (CML) Graft versus Host Reaction (GVHR)

  23. Mixed Lymphocyte Reaction (MLR)

  24. Cell-Mediated Lympholysis (CML)

  25. Delayed-Type Hypersensitivity

  26. Overview of the Delayed Type Hypersensitivity (DTH) Response

  27. Formation of Granuloma

  28. Role of IFNg in Host Defense against Intracellular Pathogens

  29. Survival of the Intracellular Pathogen

  30. Chapter 15 Leukocyte Migration and Inflammation

  31. Lymphocyte Recirculation Routes

  32. General Structures of the 4 Families of Cell-Adhesion Molecules (CAM)

  33. Cell Adhesion Molecules (CAM)

  34. Four Sequential but overlapping Steps in Neutrophil Extravasation

  35. Cell-Adhesion Molecules and Chemokines Involved in the 1st 3 Steps of Neutrophil extravasation

  36. A Lymph-Node Postcapillary Venule with High Endothelium

  37. Numerous Lymphocytes Bound to the Surface of a High Endothelial Venule (HEV)

  38. Naïve T Cells Tend to Home to Secondary Lympoid Tissues through Their HEV Regions

  39. Effector T Cells Expressing Particular Homing Receptors Will Home to particular Tertiary Extralymphoid Tissues

  40. Extravasation of a Naïve T Cell through a High Endothelial Venule into a Lymph Node

  41. Mediators of Inflammation • Chemokines • 2. Plasma Enzyme Mediators • kinin system • clotting system • fibrinolytic system • complement system • 3. Lipid Inflammatory Mediators • 4. Cytokine Inflammatory mediators

  42. Tissue Damage Induces Formation of Plasma Enzyme Mediators by the Kinin System, the Clotting System, and the Fibrinolytic System

  43. The Breakdown of Membrane Phospholipids Generates Mediators of Inflammation

  44. (proinflammatory cytokines)

  45. Overview of the Cells and Mediators Involved in a Local Acute Inflammatory Response

  46. Overview of the Organs and Mediators Involved in a Systemic Acute-Phase Response

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