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