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EFFECTOR MECHANISMS OF

CELL-MEDIATED IMMUNITY
Eradication of Intracellular Microbes
Wednesday, July 22 2009

Ika Yustisia
Department of Biochemistry
Faculty of Medicine
Hasanuddin University
Introduction
• The specialized immune mechanisms that
function to eradicate intracellular microbes
constitute cell-mediated immunity
• The effector phase of cell- mediated immunity
is carried out by T lymphocytes
– How do effector T lymphocytes locate
intracellular microbes at any site in the body?
– How do effector T cells eradicate infections by
these microbes?
Types of Cell-Mediated Immunity

There are two types of cell-mediated immune


reactions designed to eliminate different types of
intracellular microbes:
• CD4+ helper T cells activate phagocytes to destroy
microbes residing in the vesicles of these phagocytes
• CD8+ cytotoxic T lymphocytes (CTLs) kill any cell
containing microbes or microbial proteins in the
cytoplasm, thereby eliminating the reservoir of
infection
Cell-mediated immunity against intracellular microbes
The induction and effector
phases of cell-mediated
immunity
Migration of Effector T Lymphocytes
to Sites of Infection

Effector T cells migrate to sites of infection


because these lymphocytes express high levels of
adhesion molecules and chemokine receptors that
bind to ligands expressed or displayed on
endothelium after exposure to microbes and in
response to chemokines produced at the site
Migration of naive
and effector T
lymphocytes
The homing of effector T cells to a site of infection
is independent of antigen recognition, but
lymphocytes that recognize microbial antigens are
preferentially retained at the site
Migration and retention
of effector T cells
at sites of infection
Effector Functions of
CD4+ Helper T Lymphocytes

Cell-mediated immunity was discovered as a form


of immunity to an intracellular bacterial infection
that could be transferred from immune animals to
naive animals by cells (now known to be T
lymphocytes) but not by serum antibodies
Cell-mediated immunity to an intracellular bacterium
In cell-mediated immunity, CD4+ T lymphocytes of
the TH1 subset activate macrophages that have
phagocytosed microbes, resulting in increased
microbicidal activities of the phagocytes and killing
of the ingested microbes
- Delayed-type hypersensitivity (DTH)
The stages of a delayed type hypersensitivity reaction
The morphology of
a delayed-type hypersensitivity
(DTH) reaction
T CELL-MEDIATED MACROPHAGE ACTIVATION
Effector T lymphocytes of the TH1 subset that
recognize macrophage-associated antigens
activate the macrophages by CD40 ligand-CD40
interactions and by secreting the macrophage-
activating cytokine interferon-γ (IFN-γ)
Activation of macrophages by T lymphocytes
•CD4+ T lymphocytes perform functions in addition
to macrophage activation in cell-mediated immune
reactions
•Antigen-stimulated CD4+ T cells of the TH1 subset
secrete cytokines such as TNF, which act on
vascular endothelium to increase the expression of
adhesion molecules and production of chemokines
•TH17 cells may secrete chemokines that attract
neutrophils and monocytes
Cytokine-mediated interactions between T lymphocytes
and macrophages in cell-mediated immunity
ELIMINATION OF MICROBES BY ACTIVATED
MACROPHAGES
Macrophage activation leads to the expression of enzymes
that catalyze the production of microbicidal substances in
phagosomes and phagolysosomes

The major microbicidal substances produced in the


lysosomes of macrophages are reactive oxygen species
(ROS), nitric oxide (NO), and proteolytic enzymes
Activation of macrophages by T lymphocytes
Activated macrophages secrete cytokines (TNF, IL-1, and
chemokines) which stimulate the recruitment of neutrophils,
monocytes, and effector T lymphocytes to the site of
infection
Macrophages produce other cytokines, such as platelet-
derived growth factor, that stimulate the growth and
activities of fibroblasts and endothelial cells, helping to
repair tissue after the infection is cleared
ROLE OF TH2 CELLS IN CELL-MEDIATED IMMUNITY
The TH2 subset of CD4+ T lymphocytes stimulates
eosinophil-rich inflammation and also functions to limit the
injurious consequences of macrophage activation
Several cytokines produced by TH2 cells, including IL-4, IL-
10, and IL-13, inhibit the microbicidal activities of
macrophages
IL-4 and IL-13 also can activate macrophages to express
mannose receptors
IL-13 acts on fibroblasts to increase collagen synthesis and
fibrosis
This type of macrophage response is called alternative
macrophage activation, to distinguish it from classical
activation, which enhances microbicidal functions
Alternative macrophage activation mediated by
TH2 cytokines may play a role in tissue repair and
may contribute to tissue damage in the setting of
chronic parasitic infections and allergic diseases
The balance between TH1 and TH2 cell activation determines
the outcome of intracellular infections
Activated macrophages are best at killing microbes
that are confined to vesicles
Microbes that directly enter the cytoplasm (e.g.,
viruses) or escape from phagosomes into the
cytoplasm (e.g., some phagocytosed bacteria) are
relatively resistant to the microbicidal mechanisms
of phagocytes
Eradication of such pathogens requires the second
major effector mechanism of cell-mediated
immunity, namely, cytotoxic T lymphocytes (CTLs)
Effector Functions of
CD8+ Cytotoxic T Lymphocytes

CD8+ CTLs recognize class I MHC-associated


peptides on infected cells and kill those cells,
thereby eliminating the reservoir of infection
• Granzymes
• Perforin
Mechanisms of killing of
infected cells by CD8+ cytotoxic
T lymphocytes (CTLs).
Cooperation between CD4+ and CD8+ T cells
in the eradication of intracellular infections
Resistance of Pathogenic Microbes
to Cell-Mediated Immunity

Different microbes have evolved diverse


mechanisms to resist T lymphocyte-mediated host
defense
Evasion of cell-mediated
immunity by microbes