chapter 14 cell-mediated effector responses
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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 neutrophils eosinophils
Cytotoxic T Cells
Two major categories of cell-mediated immune responses:
- Effector cells that have direct cytotoxic activity.
- Effector cells that mediate delayed-type hypersensitivity (DTH) reactions
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
- The CD45RO isoform associates with the TCR complex and CD4/CD8 much better than does the CD45RA isoform.- CD2 LFA-3, LFA-1 ICAMs
- The FasL, perforins, and granzymes mediate target cell destruction by the CTLs.- Membrane-bound TNF and soluble IFN 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.
Generation of Effector CTLs
CD28B7
Tumor-Cell Destruction by a CTL
CTL
tumor cell
CTL-Mediated Killing of Target Cells
perforin monomers&
granzyme proteases
Cell-Mediated Pore Formation in Target-Cell Membrane
iCa++
fusion
release
insertion
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.
CTL Can Use Fas to Lyze a Target Cell
CTL-mediated Killing Depends on Perforin, Fas, or A Combination of the Two
CTL-Mediated Apoptotic Pathways
Caspase:cysteine, aspartate protease
Natural Killer Cells
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 IFN, IFN, and IL-12.- express CD16 (FcRIII)- 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.
Time Course of Viral Infection
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)
Opposing-signals Model of NK Activity
AR: activation receptor
KIR:killing inhibitory receptor
Ab-Dependent Cell-Mediated Cytotoxicity (ADCC)
Experimental Assessment of Cell-mediated Cytotoxicity
Mixed Lymphocyte Reaction (MLR)
Cell-mediated Lympholysis (CML)
Graft versus Host Reaction (GVHR)
Mixed Lymphocyte Reaction (MLR)
Cell-Mediated Lympholysis (CML)
Delayed-Type Hypersensitivity
Overview of the DDelayed TType HHypersensitivity (DTH) Response
Formation of Granuloma
Role of IFN in Host Defense against Intracellular Pathogens
Survival of the Intracellular Pathogen
Chapter 15
Leukocyte Migration and Inflammation
Lymphocyte Recirculation Routes
General Structures of the 4 Families of CCell-AAdhesion MMolecules (CAM)
CCell AAdhesion MMolecules (CAM)
Four Sequential but overlapping Steps in Neutrophil ExtravasationExtravasation
Cell-Adhesion Molecules and Chemokines Involved in the 1st 3 Steps of Neutrophil extravasation
A Lymph-Node Postcapillary Venule with High Endothelium
Numerous Lymphocytes Bound to the Surface of a High Endothelial Venule (HEV)
NaïveNaïve T Cells Tend to Home to Secondary Lympoid Tissues through Their HEV Regions
EffectorEffector T Cells Expressing Particular Homing Receptors Will Home to particular Tertiary Extralymphoid Tissues
Extravasation of a Naïve T Cell through aHigh Endothelial Venule into a Lymph Node
Mediators of Inflammation
1. Chemokines
2. Plasma Enzyme Mediators kinin system clotting system fibrinolytic system complement system
3. Lipid Inflammatory Mediators
4. Cytokine Inflammatory mediators
Tissue Damage Induces Formation of Plasma Plasma Enzyme MediatorsEnzyme Mediators by the Kinin System, the Clotting System, and the Fibrinolytic System
The Breakdown of Membrane Phospholipids Generates Mediators of Inflammation
(proinflammatory cytokines)
Overview of the Cells and Mediators Involved in a Local Acute Inflammatory Response
Overview of the Organs and Mediators Involved in a Systemic Acute-Phase Response
The End
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