Download Immunoregulation

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
Ag
APC
Antigen-presenting cell
Ag
Th
B cell
cell
Cytokines
Tc
cell
Granulocyte
Macrophage
Cytokines
NK
NK cell
Naïve Th Cells Can Differentiate
Into Th1 or Th2 Cells
Naive Th cells
Short-term
stimulation
Chronic
stimulation
Th1
cell
Long term
Memory cells
IFNγ
IL-2
ThP
ThO
ThM
cell
cell
cell
Th2
cell
IL-2
IFNγ
IL-2
IL-4
IL-5
IL-10
IL-4
IL-5
IL-6
IL-10
IL-2
Functions of Th1 and Th2 Cells
Th1
Th2
cell
cell
Inhibits production
IL-10
IFNγ
IL-4 IL-5
Activates
Activates
Macrophage
Mast cell
B cell
Eosinophil
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 agent
Macrophage
Antigen presentation
Macrophage
Activated macrophage
Macrophage
Th
cell
Cytokines
Lymphokines
Cytokines
Anti-microbial functions
Anti-tumor functions
Detailed Functions of Macrophages
Inflammation – Fever, Production
of: IL-6, TNF-alpha, IL-1 – act as
pyrogen
Immunity
Selection of lymphocytes to be
activated:
IL-12 results in Th1 activation
IL-4 results in Th2 activation
Activation of lymphocytes:
Production of IL-1
Processing and presentation of
antigen
Reorganization of tissues,
Secretion of a variety of factors:
Degradative enzymes (elastase,
hyaluronidase, collagenase)
Fibroblast stimulation factors
Stimulation of angiogenesis
Damage to tissues
Hydrolases, Hydrogen peroxide production
Complement C3a
TNF alpha production
Antimicrobial action
O2–dependent production of:
hydrogen peroxide, superoxide,
hydroxyl radical, hypochlorous acid
O2-independent production of:
acid hydrolases, cationic proteins,
lysozyme
Anti-tumor activity produced by:
Toxic factors
Hydrogen peroxide
Complement C3a
Proteases, Arginase
Nitric oxide
TNF 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
Macrophage
1
Activated
Macrophage
IFN gamma
TNF alpha
Th1
cell
Bacterial endotoxin
(lipopolysaccharide)
triggers cytokine
production
IFN gamma
Macrophage
2
Activated
Macrophage
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, and
2. Exposure to cytokines (IL-2 and IFN-γ)
Mechanism of Arming Tc Cells
Class I
MHC
1. Cell expressing class I MHC
presents antigen ( )
to a pre-Tc cell
3. Th cell
makes cytokines
Pre-Tc cell
IFN
IL-2
2. Antigen-presenting
cell presents antigen in
association with
class II MHC to Th cell
T helper cell
Class II MHC
APC
4. Pre-Tc cell
differentiates to
functional Tc cell
Tc cell
5. Tc recognizes antigen on
class I MHC-expressing target cell
6. Target cell
is 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
Perforin
Ca++
polymerizes
Perforin
monomers
Tc cell
Polyperforin channels
Target cell
Target cell
Granzymes
Steps in Tc Killing
Tc cell
Tc cell
Tc cell
Target cell
Target cell
Target cell
Target cell
1. Tc recognizes antigen on
target cell
2. A lethal hit is delivered by
the Tc using agents such as
perforin or granzyme B
3. The Tc detaches
from the 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 antibodydependent 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