Chapter 3

The Induced Responses of Innate Immunity

Induced responses of innate immunity

Cytokines and chemokines

Natural killer (NK) cells

Innate-like lymphocytes (ILLs)

Induced Innate Responses to Infection

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

Macrophage-derived cytokines

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

Cell-adhesion molecules control interactions

between leukocytes and endothelial cells during

an inflammatory response

Induced Innate Responses to Infection

Adhesion molecules

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

Phagocyte adhesion to vascular endothelium is mediated by integrins

Neutrophils make up the first wave of cells

that cross blood vessel wall to enter an

inflamed tissue

Induced Innate Responses to Infection

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

TNF- is an important cytokine that triggers

local containment of infection but induced shock

when released systemically

Induced Innate Responses to Infection

Both the protective and damaging effects of TNF-

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

Biological activities of IL-1, IL-6 and TNF-

Acute-phase proteins produced by liver cells

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

Biological activities of IFN against viral infection

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

NK cells as an early component of host response to viral infection

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

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

Possible mechanisms by which NK cells distinguish infected from uninfected cells

Gene encoding NK receptors

NKG2A/B – inhibitory

NKG2C/D - activating

KIR2DL/3DL – inhibitory

KIR2DS/3DS – activating

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

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

Innate-like lymphocytes and their properties

polysaccharide phospholipid glycolipid

Importance of B-1 cells in response to carbohydrate antigens