Functions of Th Cells, Th1 and Th2 Cells,

Macrophages, Tc Cells, and NK Cells; Immunoregulation

Critical Role of Th Cells in Specific Immunity

• Select effector mechanisms

• Induce proliferation in appropriate effectors

• Enhance functional activities of effectorsAPC

Thcell

B cell

Tccell

NK

AgAg

Ag

NK cell

Cytokines

GranulocyteGranulocyte MacrophageMacrophage

Cytokines

Antigen-presenting cell

Naïve Th Cells Can Differentiate Into Th1 or Th2 Cells

ThPcell

ThOcell

Th1cell

Th2cell

ThMcell

IL-12

IL-4

IL-2 IFNγIL-2IL-4IL-5IL-10

IL-4IL-5IL-6IL-10

IL-2

IFNγIL-2

Naive Th cells Short-termstimulation

Chronicstimulation

Long termMemory cells

Functions of Th1 and Th2 Cells

Th1cell

Th2cell

MacrophageMacrophage B cell

IFNγActivates

IL-4 IL-5

IL-10

Activates

Inhibits production

Inhibits proliferation

Mast cellMast cell EosinophilEosinophil

Antibodies (including IgE)

Cytokines Regulate Ig Class Switching

• Fc region of antibodies determines effector function in different anatomical locations

• Class (isotype) switching produces class or subclass of antibody most effective in host defense

• Cytokines acting alone or in combination regulate class switching

MacrophageMacrophage MacrophageMacrophage

Thcell

MacrophageMacrophage

Cytokines Lymphokines

CytokinesAnti-microbial functions

Anti-tumor functions

Activa

te

Invading agent

Antigen presentation Activated macrophage

Central Role of Macrophages in Natural and Specific Immunity

• Involved in initial defense and antigen presentation and have effector functions

Detailed Functions of MacrophagesInflammation – Fever, Production of: IL-6, TNF-alpha, IL-1 – act as pyrogen

ImmunitySelection of lymphocytes to be activated:IL-12 results in Th1 activationIL-4 results in Th2 activationActivation of lymphocytes:Production of IL-1Processing and presentation of antigen

Reorganization of tissues,Secretion of a variety of factors:Degradative enzymes (elastase, hyaluronidase, collagenase)Fibroblast stimulation factorsStimulation of angiogenesis

Damage to tissuesHydrolases, Hydrogen peroxide productionComplement C3aTNF alpha production

Antimicrobial actionO2–dependent production of: hydrogen peroxide, superoxide, hydroxyl radical, hypochlorous acidO2-independent production of: acid hydrolases, cationic proteins, lysozyme

Anti-tumor activity produced by:Toxic factorsHydrogen peroxideComplement C3aProteases, ArginaseNitric oxideTNF alpha

Macrophage Activation Macrophage activation results from

alterations in gene products that govern new functions.

Two major mechanisms that activate macrophages:

• IFN-γ produced by Th or Th1 cells plus bacterial endotoxin (LPS)

• IFN-γ produced by Th or Th1 cells plus TNF-α

Mechanism of Macrophage Activation

MacrophageMacrophage ActivatedMacrophageActivatedMacrophage

Bacterial endotoxin(lipopolysaccharide)

triggers cytokine productionTh1

cell

1

IFN gamma

IFN gamma

2MacrophageMacrophage

ActivatedMacrophageActivatedMacrophage

TNF alpha

Various products

Cytolytic T (Tc) Cells

• Tc exiting the thymus are pre-Tc cells, i.e. have TCR that can recognize antigen, but are not mature and cannot kill until “armed”

• To become armed requires two signals:1. Recognition by TCR of specific antigen

associated with class I MHC, and2. Exposure to cytokines (IL-2 and IFN-γ)

Mechanism of Arming Tc Cells

Pre-Tc cell

Tc cell

T helper cell

Class IMHC

Class II MHCAPC

1. Cell expressing class I MHC presents antigen ( )

to a pre-Tc cell

IFNIL-2

2. Antigen-presenting cell presents antigen in

association with class II MHC to Th cell3. Th cell

makes cytokines

4. Pre-Tc celldifferentiates to

functional Tc cell

5. Tc recognizes antigen onclass I MHC-expressing target cell

6. Target cellis killed

Features of Tc Killing

• Antigen-specific

• Requires cell-cell contact

• Each Tc capable of killing many target cells

Main Mechanism of Tc Killing

• Tc granules contain perforin and granzymes

• Upon contact with target cell, granule contents released, perforin polymerizes and forms channel in target cell membrane

• Granzymes (serine proteases) enter target cell through channel, activate caspases and nucleases, lead to apoptosis of target cell

Mechanism of Tc Killing

Tc cell

Ca++

Perforinmonomers

Perforinpolymerizes

Polyperforin channels

Tc cell

Target cell

Granzymes

Target cell

Steps in Tc Killing

Tc cell1. Tc recognizes antigen ontarget cell

Target cell

Tc cell

2. A lethal hit is delivered by the Tc using agents such as perforin or granzyme B

Target cell

Tc cell

3. The Tc detaches from the target cellTarget cell

4. Target cell dies by apoptosis

Target cell

Natural Killer (NK) Cells • Derived from bone marrow• Lack most markers for T and B cells (do not have

TCR)• Do not undergo thymic maturation• Express CD56, a specific NK marker• Express a receptor for Fc portion of IgG, called

FcRIII (CD16)• Cytokines (IL-2) promote differentiation into

lymphokine-activated killer (LAK) cells

NK Cell Effector Mechanisms

• Mechanism of killing similar to those of Tc cells

• Not MHC-restricted

• Susceptibility of target cell to killing is inversely proportional to expression of class I MHC (killer inhibitory receptors (KIR) on NK cells recognize class I MHC and prevent killing)

NK Effector Mechanisms(continued)

• IgG-coated target cells recognized by FcRIII (CD16) are killed by antibody-dependent cell-mediated cytotoxicity (ADCC)

• Lymphokine-activated killer cells (LAK) kill broader range of cells than do NK cells

Regulation of Immune Responses• Magnitude determined by balance between

the extent of lymphocyte activation and tolerance induced by an antigen

• Nature determined by specificities and functional classes of lymphocytes activated

• Regulatory mechanisms may act at the recognition, activation, or effector phases of an immune response