CMI

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 effectors

APC

TH

cell

B cell

Tccell NK

Ag

Ag

Ag

NK cell

Cytokines

GranulocyteGranulocyte MacrophageMacrophage

Cytokines

Antigen-presenting cell

Ag

T Cell-B Cell Interactions(hapten-carrier effect)

• TH cells recognize carrier APC

• B cells recognize hapten (Soluble Ag)

• TH and B cells cooperate by interacting

• Interactions are class II self-MHC restricted

Uniqueness of B Cells

• Express both immunoglobulin (Ig) and class II MHC on cell surface

• Capable of producing antibody of same specificity as that of its surface Ig

AND• Capable of functioning as an antigen

presenting cell

Mechanism of Hapten-Carrier• Hapten recognized by Ig receptor on B cell

• Hapten-carrier endocytosed

• Carrier processed and presented on class II MHC to TH cell

• Activated TH cell produces cytokines

• Cytokines enable B cell to be activated to produce anti-hapten antibodies

Antigen

1. Antigen presentation toTH cell

2. B7 expressed 3. Th cell is activated

and expresses CD40 ligand,

Cytokines secreted

CD40

Immunoglobulinreceptor

MHC II

Cytokine receptor

Bcell

Cytokine

CD40 ligand

Bcell

T helpercell

4. Cytokine binds to cytokine receptor,

CD40 ligand binds to CD40

Bcell

Bcell

Bcell

5. B cell activated

6. B cells proliferate, differentiate, secrete Ig

B7B7B7B7 CD28

TCRTCRTCRTCRT helpercell

Bcell

Class II MHCAPCTH cell B

cell

Bcell

Bcell

B cell takes up and presents antigen

TH cell

Bcell

Th cells are primed by antigen-presenting cell

B-T cell cooperationB cells receive signals from T cells

B cells divide

Bcell

Bcell

Bcell

Bcell

Antibody formingcell

Antibody formingcell

Antibody formingcell

Antibody formingcell

Antibody formingcell

Antibody formingcell

Bmemory

cell

B Cells In Secondary Responses

• Memory cells created during primary response

• Have high-affinity Ig receptors

• Can therefore take up antigens at much lower concentrations than other antigen presenting cells that lack Ig antigen receptors

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

TH

cell

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

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

Class IMHC

1. Cell expressing class I MHC presents antigen ( )

to a pre-Tc cell

2. Pre-Tc celldifferentiates to

functional Tc cell

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

4. 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