Transcript 2. Cell-mediated immunity

Monocytes in Immune Defense
& Cell-mediated Cytotoxicity
• Pin Ling (凌 斌), Ph.D.
ext 5632; [email protected]
• References:
1. Male D., J. Brostoff, D. B Roth, and I.
Roitt Immunology (7th ed., 2006),
Chapters 9 & 10
Question
What happens to the immune system
if RAG1 or RAG2 is mutated?
1. Severe Combined Immunodeficiency Disease
(SCID)
2. Lacking functional T & B cells
Outline
• Cell-mediated immunity
• Monocytes/Macrophages in immune
defense
• NK & Cytotoxic T cells in immune
defense
• Summary & Question
Humoral vs Cellmediated immunity
1. Humoral immunity
=> Molecules in body fluid,
e.g. Antibody (Ab)
=> Key player => B cells
=> Target
extracellular
For
innate
immunity, it
microbes
& toxins
Cellular
components
for
2. Cell-mediated immunity
=> Key player => MΦ, NK,
& T cells
=> regulate other immune
cells
=> Target intracellular
microbes, e.g. viruses,
bacteria
also includes Humoral &
immune defense
Key Concepts in Monocytic
Phagocytes in Immune Defense-I
1. Macrophages differentiate from circulating blood
monocytes.
2. Macrophages are very heterogeneous in cellular
activities, and may play positive or negative roles in
immune defense and tissue homeostasis.
3. Tissue (Resident) & recruited macrophages respond to
injury and immune stimuli.
4. Cytokines, Chemokines, & environmental stimuli
modulate the phenotype of macrophages.
Maturation of Macrophages
Activated Macro
Differentiation of
Monocytes
Tissue MΦ
 Localized MΦ
 Regulated by
environmental stimuli
Different types of tissue macrophages
Roles of macrophages & DCs in
immune defense
Cytokines modulate the
phenotype of macrophages-I
Cytokines/environmental
stimuli on macrophages
Granuloma in pulmonary tuberculosis
Cytokines modulate the
phenotype of macrophages-II
Th1 & Th2 cytokines act on
macrophages
Key Concepts in Monocytic
Phagocytes in Immune Defense-II
1. Macrophages use phagocytosis to kill invading
pathogens and to clean apoptotic cells.
2. Macrophages express a variety of surface receptors
to interact with pathogens, other cells (apoptotic
cells), or environment.
3. Opsonic receptors, like Fc (for Ab) & complment
receptors, mediate indirect binding (Opsonization) to
pathogens.
4. Non-opsonic receptors, like Scavenger & Toll-like
receptors, mediate direct binding to pathogenic
components (PAMPs).
Phagocytosis of bacteria by opsonic
receptors on macrophages
Fc & complement receptors on
macrophages for uptaking bacteria
Recognition of bacteria by
Macrophage
Direct binding
Opsonization
Scavenger receptors recognize
apoptotic cells
Lectin-like receptors bind various
sugar ligands from pathogens
TLR4/MD2 and CD14 complex for
LPS recognition
TLR-mediated IFN-b activation
against viral infection
Macrophages have intracellular
receptors for detecting pathogens
Macrophages produce a variety of
secreted molecules
ROS-mediated killing bacteria in
activated macrophages
NOS pathway in activated
macrophages
Roles of activated macrophages
in immunopathology
Outline
• Cell-mediated immunity
• Monocytes/Macrophages in immune
defense
• NK cells & Cytotoxic T lymphocytes
(CTLs) in immune defense
• Summary & Question
Key concepts in NK & CTL
in immune defense
1. Cell-mediated cytotoxicity is an essential defense
against intracellular pathogens, including viruses, some
bacteria and parasites.
2. Cytotoxicity is regulated by celluar interactions,
cytokines, and granule exocytosis.
3. CTLs recognize their target cells presenting Ag on
MHC-I. NK cells are activated once their target cells
lost MHC-I.
4. Tumor cells may also become the targets of cytotoxic
cells
Recognition of target cells by
CTLs and NK cells
Interactions between CTLs
and target cells
Effector functions of CTLs
and CD4+ T helper cells
Granule exocytosis of CTLs-I
Granule exocytosis of CTLs-II
Figure 8-35
CTLs induce apoptosis in target cells
Ligation of Fas (CD95) or TNFR
triggers apoptosis in target cells
Figure 2-49
Activation of NK
cells once target
cells lost MHC-I
1. Virus-infected cells
& tumor cells tend
to lost MHC-I to
avoid CTL attack.
2. NK cells are
complementary to
CTLs for immune
defense.
NK cells express a variety of inhibitory
& activating receptors
CD94-NKG2A
CD94-NKG2C
HLA-E presents peptides of MHC-I to
NK cells
Killer immunoglobulin-like receptors
(KIRs)
Ab-dependent cell-mediated
cytotoxicity (ADCC) by NK cells
SUMMARY
1.
Macrophages are key players in innate immunity and
also link to adaptive immunity.
2.
Macrophages use phagocytosis to kill invading
pathogens and to clean apoptotic cells.
3.
NK cells also play a key role in innate immunity and
function complementary to CTLs against viruses and
tumors.
4. Cell-mediated cytotoxicity is an essential defense
against intracellular pathogens, including viruses, some
bacteria and parasites.
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© 2005 Elsevier
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© 2005 Elsevier
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© 2005 Elsevier
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© 2005 Elsevier
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© 2005 Elsevier
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© 2005 Elsevier
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© 2005 Elsevier
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© 2005 Elsevier
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© 2005 Elsevier
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© 2005 Elsevier
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© 2005 Elsevier
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© 2005 Elsevier
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Granuloma in pulmonary tuberculosis
Figure 8-27
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© 2005 Elsevier