Cell-Mediated Effector

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Chapter 14 Cell-Mediated Effector
Responses
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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
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Cytotoxic T Cells
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• Two major categories of cell-mediated immune
  responses
• Effector cells that have direct cytotoxic
  activity.
• Effector cells that mediate delayed-type
• hypersensitivity (DTH) reactions

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

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• - 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.

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Generation of Effector CTLs
B7
CD28
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Naïve CTL-Ps Need Help from TH1 Cells to
provide IL-2
paracrine
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Memory CTL-Ps Appear to Secrete Sufficient IL-2
to Stimulate Their Own Proliferation and
Differentiation into Effector CTLs
autocrine
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Tumor-Cell Destruction by a CTL
CTL
tumor cell
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CTL-Mediated Killing of Target Cells
perforin monomers granzyme proteases
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Cell-Mediated Pore Formation in Target-Cell
Membrane
fusion
release
iCa?
insertion
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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.

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CTL Can Use Fas to Lyze a Target Cell
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CTL-mediated Killing Depends on Perforin, Fas,
or A Combination of the Two
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CTL-Mediated Apoptotic Pathways
Caspase cysteine, aspartate protease
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Natural Killer Cells
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• 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.

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Time Course of Viral Infection
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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 (gt 50 members specific for
one or a limited number of
polymorphic products of particular HLA loci)
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Opposing-signals Model of NK Activity
KIR killing inhibitory receptor
AR activation receptor
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Ab-Dependent Cell-Mediated Cytotoxicity (ADCC)
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Experimental Assessment of Cell-mediated
Cytotoxicity Mixed Lymphocyte Reaction
(MLR) Cell-mediated Lympholysis (CML) Graft
versus Host Reaction (GVHR)
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Mixed Lymphocyte Reaction (MLR)
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Cell-Mediated Lympholysis (CML)
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Delayed-Type Hypersensitivity
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Overview of the Delayed Type Hypersensitivity
(DTH) Response
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Formation of Granuloma
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Role of IFNg in Host Defense against
Intracellular Pathogens
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Survival of the Intracellular Pathogen
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Chapter 15 Leukocyte Migration
and Inflammation
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Lymphocyte Recirculation Routes
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General Structures of the 4 Families of
Cell-Adhesion Molecules (CAM)
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Cell Adhesion Molecules (CAM)
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Four Sequential but overlapping Steps in
Neutrophil Extravasation
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Cell-Adhesion Molecules and Chemokines Involved
in the 1st 3 Steps of Neutrophil extravasation
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A Lymph-Node Postcapillary Venule with High
Endothelium
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Numerous Lymphocytes Bound to the Surface of a
High Endothelial Venule (HEV)
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Naïve T Cells Tend to Home to Secondary Lympoid
Tissues through Their HEV Regions
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Effector T Cells Expressing Particular Homing
Receptors Will Home to particular Tertiary
Extralymphoid Tissues
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Extravasation of a Naïve T Cell through a High
Endothelial Venule into a Lymph Node
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• Mediators of Inflammation
• Chemokines
• 2. Plasma Enzyme Mediators
• kinin system
• clotting system
• fibrinolytic system
• complement system
• 3. Lipid Inflammatory Mediators
• 4. Cytokine Inflammatory mediators

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Tissue Damage Induces Formation of Plasma Enzyme
Mediators by the Kinin System, the Clotting
System, and the Fibrinolytic System
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The Breakdown of Membrane Phospholipids
Generates Mediators of Inflammation
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(proinflammatory cytokines)
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Overview of the Cells and Mediators Involved in
a Local Acute Inflammatory Response
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Overview of the Organs and Mediators Involved in
a Systemic Acute-Phase Response
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The End