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
Ag APC
Ag Antigen-presenting cell
Ag

Th B cell
cell

Cytokines
Tc
Granulocyte Macrophage NK
cell
NK cell
Cytokines
 Nave Th Cells Can Differentiate
Into Th1 or Th2 Cells
Naive Th cells Short-term Chronic Long term
stimulation stimulation Memory cells
IFN
Th1 IL-2
-12 cell
IL
ThP ThO ThM
cell cell IL- cell
4
Th2
cell

IL-2 IFN IL-2

IL-2 IL-4
IL-4 IL-5
IL-5 IL-6
IL-10 IL-10
Functions of Th1 and Th2 Cells
Th1 Th2
cell a tion cell
r
life
s pro
t
h ibi
In
Inhibits production
IL-10

IFN IL-4 IL-5

Activates Activates

Macrophage B cell Eosinophil

Mast cell

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
Central Role of Macrophages in
Natural and Specific Immunity
Involved in initial defense and antigen
presentation and have effector functions
Invading Antigen presentation Activated
agent macrophage

Macrophage Macrophage Macrophage

Th

ate
cell
tiv
Ac

Cytokines
Cytokines Lymphokines Anti-microbial functions
Anti-tumor functions
 Detailed Functions of Macrophages
Inflammation Fever, Production Damage to tissues
of: IL-6, TNF-alpha, IL-1 act as Hydrolases, Hydrogen peroxide production
pyrogen Complement C3a
TNF alpha production
Immunity Antimicrobial action
Selection of lymphocytes to be
O2dependent production of:
activated:
hydrogen peroxide, superoxide,
IL-12 results in Th1 activation
hydroxyl radical, hypochlorous acid
IL-4 results in Th2 activation
O2-independent production of:
Activation of lymphocytes:
acid hydrolases, cationic proteins,
Production of IL-1
lysozyme
Processing and presentation of
antigen Anti-tumor activity produced by:
Toxic factors
Reorganization of tissues, Hydrogen peroxide
Secretion of a variety of factors:
Complement C3a
Degradative enzymes (elastase,
Proteases, Arginase
hyaluronidase, collagenase)
Nitric oxide
Fibroblast stimulation factors
TNF alpha
Stimulation of angiogenesis
 Macrophage Activation
Macrophage activation results from
alterations in gene products that govern
new functions.
Two major mechanisms that activate
macrophages:
IFN- produced by Th or Th1 cells plus
bacterial endotoxin (LPS)
IFN- produced by Th or Th1 cells plus
TNF-
Mechanism of Macrophage Activation
Macrophage 1 Activated
Macrophage
IFN gamma Bacterial endotoxin
TNF alpha
(lipopolysaccharide)
triggers cytokine
Th1 production
cell
IFN gamma

2 Activated Various
Macrophage Macrophage 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, and
2. Exposure to cytokines (IL-2 and IFN-)
 Mechanism of Arming Tc Cells
1. Cell expressing class I MHC
Class I presents antigen ( ) 2. Antigen-presenting
MHC to a pre-Tc cell cell presents antigen in
association with
3. Th cell class II MHC to Th cell
makes cytokines

Pre-Tc cell IFN T helper cell Class II MHC

IL-2 APC
4. Pre-Tc cell
differentiates to
functional Tc cell

Tc cell
6. Target cell
5. Tc recognizes antigen on is killed
class I MHC-expressing target cell
 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 Tc cell Granzymes

Perforin
monomers
Perforin Ca++
polymerizes

Polyperforin channels
Target cell Target cell
 Steps in Tc Killing
1. Tc recognizes antigen on
Target cell
Tc cell target cell

2. A lethal hit is delivered by

Tc cell Target cell the Tc using agents such as
perforin or granzyme B

3. The Tc detaches
Target cell from the target cell
Tc cell

Target cell 4. Target cell dies

by apoptosis
 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