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Chapter 3
The Induced Responses of Innate Immunity
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Induced responses of innate immunity
Cytokines and chemokines
Natural killer (NK) cells
Innate-like lymphocytes (ILLs)
Induced Innate Responses to Infection
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Macrophages and DCs activated by pathogens secret a range of cytokines that have a variety of local and distant effects
Cytokines
Small proteins ( 25kDa)
Bind to cytokine receptors
Affect behavior of cells
autocrine – cells releasing the cytokines
paracrine - adjacent cells
endocrine - distant cells
Induced Innate Responses to Infection
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Macrophage-derived cytokines
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Chemokines released by phagocytes and dendritic cells recruit cells to sites of infection Chemokines
Small chemoattractant cytokines
Bind to chemokine receptors
Multiple functions
chemoattractants for leukocytes
lymphocyte development and migration
angiogenesis
Induced Innate Responses to Infection
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Cell-adhesion molecules control interactions
between leukocytes and endothelial cells during
an inflammatory response
Induced Innate Responses to Infection
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Adhesion molecules
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Cell-adhesion molecules control interactions between leukocytes and endothelial cells during an inflammatory response
Adhesion molecules
TNF- from macrophage activates endothelial cells
induces P-selectin on EC within mins
induces E-selectin on EC within 2 hrs
induces ICAM-1, which binds to LFA-1 or CR3 on circulating monocytes and neutrophils
ICAM-2 on resting EC may be used by circulating monocytes to navigate into tissue sites
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Phagocyte adhesion to vascular endothelium is mediated by integrins
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Neutrophils make up the first wave of cells
that cross blood vessel wall to enter an
inflamed tissue
Induced Innate Responses to Infection
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Extravasation occurs in four steps
Neutropenia:
Patients who have reduced numbers of neutrophils are very susceptible to infection with wide range of pathogens and commensal organisms
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TNF- is an important cytokine that triggers
local containment of infection but induced shock
when released systemically
Induced Innate Responses to Infection
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Both the protective and damaging effects of TNF-
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Cytokines released by macrophages and DCs activate the acute-phase response
Multiple effects of cytokines from macrophages on host
IL-1,6 increase body temperature:endogenous pyrogens
TNF-, IL-1, IL-6 induce acute-phase proteins
C-reactive protein (phosphocholine)
Mannose-binding lectin
Surfactant protein SP-A and SP-D
Leukocytosis – increase in circulating neutrophils
Induced Innate Responses to Infection
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Biological activities of IL-1, IL-6 and TNF-
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Acute-phase proteins produced by liver cells
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Interferons induced by viral infection make several contributions to host defense
TLR3 or RIG-I/MDA-5 recognize viral RNAs and produce interferon (IFN)
Type I IFN (/) contribute to defense viral infection
1) Induction of resistance to viral infection in all cells
Janus kinaseSTATendoribonucleasevRNA
PKR kinaseeIF-2translation
2) Increasing T cell response to viral infection
– induction of MHC class I expression
Induced Innate Responses to Infection
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Biological activities of IFN against viral infection
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NK cells are activated by IFN and macrophage-derived cytokines to serve as an early defense against certain intracellular infections
NK cells are able to kill tumor cell without activation
NK cells have effector proteins to kill infected cells
NK cell killing is triggered by receptor recognizing components of infected cells
Upon exposure to IFN-/, the killing activity is increased by 20-100 times
IL-12, in synergy with TNF-, elicits IFN- production
Induced Innate Responses to Infection
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NK cells as an early component of host response to viral infection
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NK cells possess receptors for self molecules that prevent their activation by uninfected cells
NK cells are able to recognize ‘altered self’
NK cells have two types of receptors
Activating vs inhibitory receptors
C-type lectins (NKC) vs Ig-like receptors (KIR)
NK cells have receptor for Ig - ADCC
Induced Innate Responses to Infection
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NK cells possess receptors for self molecules that prevent their activation by uninfected cells
Mechanisms by which NK cells recognize and kill infected cells
recognizing lowered MHC class I expression on infected cell surface
- reduced MHC class I protein synthesis
- reduced MHC class I export
altered glycosylation of cellular proteins
Induced Innate Responses to Infection
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Possible mechanisms by which NK cells distinguish infected from uninfected cells
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Gene encoding NK receptors
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NKG2A/B – inhibitory
NKG2C/D - activating
KIR2DL/3DL – inhibitory
KIR2DS/3DS – activating
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NK cells bear receptors that activate their effector function in response to ligands expressed on infected cells or tumor cells
Natural cytotoxicity receptors – NKp30, NKp44, NKp46
NKG2D – MIC-A/MIC-B and RAET1
Ligands for NKG2D are expressed on infected cells as well as on tumor cells
Induced Innate Responses to Infection
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Several lymphocyte subpopulations behave as
innate-like lymphocytes
Innate-like lymphocytes (ILL)
a very limited diversity of receptors
occur only in specific locations
do not undergo clonal expansion
T cells, B-1 cells, NKT cells
Natural antibodies - IgM
Induced Innate Responses to Infection
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Innate-like lymphocytes and their properties
polysaccharide phospholipid glycolipid
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Importance of B-1 cells in response to carbohydrate antigens