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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 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.
Generation of Effector CTLs
B7
CD28
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
fusion
release
iCa++
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 apoptotic 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 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.
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
KIR:
killing inhibitory receptor
AR:
activation 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 Delayed Type Hypersensitivity
(DTH) Response
Formation of Granuloma
Role of IFNg 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 Cell-Adhesion Molecules (CAM)
Cell Adhesion Molecules (CAM)
Four Sequential but overlapping Steps
in Neutrophil Extravasation
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)
Naïve T Cells Tend to Home to Secondary
Lympoid Tissues through Their HEV Regions
Effector T Cells Expressing Particular Homing Receptors
Will Home to particular Tertiary Extralymphoid Tissues
Extravasation of a Naïve T Cell through a
High 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
Enzyme 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