Introduction to the Immune System (The Immune System in Health and Disease) (Rheumatology) Part 2

Pattern Recognition

Major PRR families of proteins include C-type lectins, leucine-rich proteins, macrophage scavenger receptor proteins, plasma pentraxins, lipid transferases, and inte-grins (Table 1-3).A major group of PRR collagenous glycoproteins with C-type lectin domains are termed collectins and include the serum protein mannose-binding lectin (MBL). MBL and other collectins, as well as two other protein families—the pentraxins (such as C-reactive protein and serum amyloid P) and macrophage scavenger receptors—all have the property of opsonizing (coating) bacteria for phagocytosis by macrophages and can also activate the complement cascade to lyse bacteria. Integrins are cell-surface adhesion molecules that signal cells after cells bind bacterial lipopolysaccharide (LPS) and activate phagocytic cells to ingest pathogens.

A series of recent discoveries has revealed the mechanisms of connection between the innate and adaptive immune systems; these include (1) a plasma protein, LPS-binding protein, which binds and transfers LPS to the macrophage LPS receptor, CD14; and (2) a human family of proteins called Toll-like receptor proteins (TLR), some of which are associated with CD14, bind LPS, and signal epithelial cells, dendritic cells, and macrophages to produce cytokines and upregulate cell-surface molecules that signal the initiation of adaptive immune responses (Fig. 1-1,Tables 1-3, 1-4). Proteins in the Toll family (TLR 1-10) can be expressed on macrophages, dendritic cells, and B cells as well as on a variety of nonhematopoietic cell types, including respiratory epithelial cells (Tables 1-4, 1-5). Upon ligation, these receptors activate a series of intracellular events that lead to the killing of bacteria- and viral-infected cells as well as to the recruitment and ultimate activation of antigen-specific T and B lymphocytes (Fig. 1-1). Importantly, signaling by massive amounts of LPS through TLR4 leads to the release of large amounts of cytokines that mediate LPS-induced shock. Mutations in TLR4 proteins in mice protect from LPS shock, and TLR mutations in humans protect from LPS-induced inflammatory diseases such as LPS-induced asthma (Fig. 1-1).


Overview of major TLR signaling pathways. All TLRs signal through MyD88, with the exception of TLR3. TLR4 and the TLR2 subfamily (TLR1, TLR2, TLR6) also engage TIRAP TLR3 signals through TRIF. TRIF is also used in conjunction with TRAM in the TLR4-MyD88-independent pathway. Dashed arrrows indicate translocation into the nucleus. LPS, lipopolysaccharide; dsRNA, double-strand RNA; ssRNA, single-strand RNA; MAPK, mitogen-activated protein kinases; NF-KB, nuclear factor-KB; IRF3, interferon regulatory factor 3.

FIGURE 1-1

Overview of major TLR signaling pathways. All TLRs signal through MyD88, with the exception of TLR3. TLR4 and the TLR2 subfamily (TLR1, TLR2, TLR6) also engage TIRAP TLR3 signals through TRIF. TRIF is also used in conjunction with TRAM in the TLR4-MyD88-independent pathway. Dashed arrrows indicate translocation into the nucleus. LPS, lipopolysaccharide; dsRNA, double-strand RNA; ssRNA, single-strand RNA; MAPK, mitogen-activated protein kinases; NF-KB, nuclear factor-KB; IRF3, interferon regulatory factor 3.

TABLE 1-4

THE ROLE OF PRRS IN MODULATION OF T CELL RESPONSES

PRR

FAMILY

PRRS

LIGAND

DC OR MACROPHAGE CYTOKINE RESPONSE

ADAPTIVE IMMUNE RESPONSE

TLRs

TLR2

Lipopeptides

Low IL-12p70

Th1

(heterodimer

Pam-3-cys (TLR 2/6)

High IL-10

Th2

with TLR1 or 6)

MALP (TLR 2/1)

IL-6

T regulatory

TLR3

dsRNA

IL-12p70

Th1

IFN-α

IL-6

TLR4

E. coli LPS

High IL-12p70

Th1

Intermediate IL-10

IL-6

TLR5

Flagellin

High IL-12p70

Th1

Low IL-12p70

TH2

TLR7/8

ssRNA

High IL-12p70

Th1

Imidazoquinolines

IFN-α

IL-6

TLR9

CpG DNA

High IL-12p70

TH1

Low IL-10

IL-6

IFN-α

TLR10

DC-SIGN

?

?

?

C-type

lectins

Env of HIV; core protein of HCV; components of M. tuberculosis;

H. pylori, Lewis Ag

H. pylori, Lewis Ag

TH2

Suppresses IL-12p70

Suppression of TLR signaling in DCs

T regulatory

NOD

NOD2

Muramyl dipeptide of peptidoglycan

Induces IL-10 in DCs

Weak T cell response (tolerogenic?)

Mannose

receptor

Mannose

receptor

Mannosylated lipoarabinomannans from bacillus Calmette-Guerin and M. tuberculosis

Suppression of IL-12 and TLR signaling in DCs

Weak T cell response? (tolerogenic?)

Note: dsRNA, double-strand RNA; ssRNA, single-strand RNA; LPS, lipopolysaccharide; TH2, helper T cell; TH1, helper T cell; CpG, sequences in DNA recognized by TLR-9; MALP, macrophage-activating lipopeptide; DC-SIGN, DC-specific C-type lectin; NOD, NOTCH protein domain; TLR, Toll-like receptor; HIV, human immunodeficiency virus; HCV, hepatitis C.

Cells of invertebrates and vertebrates produce antimicrobial small peptides (<100 amino acids) that can act as endogenous antibodies (Table 1-2). Some of these peptides are produced by epithelia that line various organs, while others are found in macrophages or neutrophils that ingest pathogens. Antimicrobial peptides have been identified that kill bacteria such as Pseudomonas spp., Escherichia coli, and Mycobacterium tuberculosis.

Effectors Cells’ of Innate Immunity

Cells of the innate immune system and their roles in the first line of host defense are listed in Table 1-5. Equally important as their roles in the mediation of innate immune responses are the roles that each cell type plays in recruiting T and B lymphocytes of the adaptive immune system to engage in specific antipathogen responses.

Monocytes-Macrophages

Monocytes arise from precursor cells within bone marrow (Fig. 1-2) and circulate with a half-life ranging from 1 to 3 days. Monocytes leave the peripheral circulation by marginating in capillaries and migrating into a vast extravascular pool. Tissue macrophages arise from monocytes that have migrated out of the circulation and by in situ proliferation of macrophage precursors in tissue. Common locations where tissue macrophages (and certain of their specialized forms) are found are lymph node, spleen, bone marrow, perivascular connective tissue, serous cavities such as the peritoneum, pleura, skin connective tissue, lung (alveolar macrophages), liver (Kupffer cells),bone (osteoclasts), central nervous system (microglia cells), and synovium (type A lining cells).

TABLE 1-5

CELLS OF THE INNATE IMMUNE SYSTEM AND THEIR MAJOR ROLES IN TRIGGERING ADAPTIVE IMMUNITY

CELL TYPE

MAJOR ROLE IN INNATE IMMUNITY

MAJOR ROLE IN ADAPTIVE IMMUNITY

Macrophages

Phagocytose and kill bacteria; produce antimicrobial peptides; bind (LPS); produce inflammatory cytokines

Produce IL-1 and TNF-α to upregulate lymphocyte adhesion molecules and chemokines to attract antigen-specific lymphocyte. Produce IL-12 to recruit TH1 helper T cell responses; upregulate co-stimulatory and MHC molecules to facilitate T and B lymphocyte recognition and activation. Macrophages and dendritic cells, after LPS signaling, upregulate co-stimulatory molecules B7-1 (CD80) and B7-2 (CD86) that are required for activation of antigen-specific anti-pathogen T cells. There are also Toll-like proteins on B cells and dendritic cells that, after LPS ligation, induce CD80 and CD86 on these cells for T cell antigen presentation

Plasmacytoid f dendritic cells (DCs) of lymphoid lineage

Produce large amounts of interferon-α (IFN-α), which has antitumor and antiviral activity, and are found in T cell zones of lymphoid organs; they circulate in blood

IFN-α is a potent activator of macrophage and mature DCs to phagocytose invading pathogens and present pathogen antigens to T and B cells

Myeloid dendritic cells are of two types; interstitial and

Interstitial DCs are strong producers of IL-12 and IL-10 and are located in

Interstitial DCs are potent activator of macrophage and mature DCs to phagocytose invading pathogens and present pathogen antigens to T and B cells

T cell zones of lymphoid organs, circulate in blood, and are present in the interstices of the lung, heart, and kidney; Langerhans DCs are strong producers of IL-12; are located in T cell zones of lymph nodes, skin epithelia, and the thymic medulla; and circulate in blood

Langerhans-derived

Natural killer (NK) cells

Kill foreign and host cells that have low levels of MHC+ self-peptides. Express NK receptors that inhibit NK function in the presence of high expression of self-MHC

Produce TNF-α and IFN-γ that recruit TH1 helper T cell responses

NK-T cells

Lymphocytes with both T cell and NK surface markers that recognize lipid antigens of intracellular bacteria such as M. tuberculosis by CD1 molecules and kill host cells infected with intracellular bacteria

Produce IL-4 to recruit TH2 helper T cell responses, IgG1 and IgE production

Neutrophils

Phagocytose and kill bacteria, produce antimicrobial peptides

Produce nitric oxide synthase and nitric oxide that inhibit apoptosis in lymphocytes and can prolong adaptive immune responses

Eosinophils

Kill invading parasites

Produce IL-5 that recruits Ig-specific antibody responses

Mast cells and basophils

Release TNF-α, IL-6, IFN-γ in response to a variety of bacterial PAMPs

Produce IL-4 that recruits TH2 helper T cell responses and recruit IgG1- and IgE-specific antibody responses

Epithelial cells

Produce anti-microbial peptides; tissue specific epithelia produce mediator of local innate immunity, e.g., lung epithelial cells produce surfactant proteins (proteins within the collectin family) that bind and promote clearance of lung invading microbes

Produces TGF-β that triggers IgA-specific antibody responses.

Note: LPS, lipopolysaccharide; PAMP, pathogen-associated molecular patterns; TNF-α, tumor necrosis factor-alpha; IL-4, IL-5, IL-6, IL-10, and IL-12, interleukin 4, 5, 6, 10, and 12, respectively.

Schematic model of intercellular interactions of adaptive immune system cells. In this figure the arrows denote that cells develop from precursor cells or produce cytokines or antibodies; lines ending with bars indicate suppressive intercellular interactions. Stem cells differentiate into either T cells, antigen-presenting dendritic cells, natural killer cells, macrophages, granulocytes, or B cells. Foreign antigen is processed by dendritic cells, and peptide fragments of foreign antigen are presented to CD4+ and/or CD8+ T cells. CD8+ T cell activation leads to induction of cytotoxic T lymphocyte (CTL) or killer T cell generation, as well as induction of cytokine-producing CD8+ cytotoxic T cells. For antibody production against the same antigen, active antigen is bound to sIg within the B cell receptor complex and drives B cell maturation into plasma cells that secrete Ig. TH1 or TH2 CD4+ T cells producing interleukin (IL) 4, IL-5, or interferon (IFN)y regulate the Ig class switching and determine the type of antibody produced. CD4+, CD25+ T regulatory cells produce IL-10 and downregulate T and B cell responses once the microbe has been eliminated. GM-CSF, granulocyte-macrophage colony stimulating factor; TNF, tumor necrosis factor.

FIGURE 1-2

Schematic model of intercellular interactions of adaptive immune system cells. In this figure the arrows denote that cells develop from precursor cells or produce cytokines or antibodies; lines ending with bars indicate suppressive intercellular interactions. Stem cells differentiate into either T cells, antigen-presenting dendritic cells, natural killer cells, macrophages, granulocytes, or B cells. Foreign antigen is processed by dendritic cells, and peptide fragments of foreign antigen are presented to CD4+ and/or CD8+ T cells. CD8+ T cell activation leads to induction of cytotoxic T lymphocyte (CTL) or killer T cell generation, as well as induction of cytokine-producing CD8+ cytotoxic T cells. For antibody production against the same antigen, active antigen is bound to sIg within the B cell receptor complex and drives B cell maturation into plasma cells that secrete Ig. TH1 or TH2 CD4+ T cells producing interleukin (IL) 4, IL-5, or interferon (IFN)y regulate the Ig class switching and determine the type of antibody produced. CD4+, CD25+ T regulatory cells produce IL-10 and downregulate T and B cell responses once the microbe has been eliminated. GM-CSF, granulocyte-macrophage colony stimulating factor; TNF, tumor necrosis factor.

In general, monocytes-macrophages are on the first line of defense associated with innate immunity and ingest and destroy microorganisms through the release of toxic products such as hydrogen peroxide (H2O2) and nitric oxide (NO). Inflammatory mediators produced by macrophages attract additional effector cells such as neutrophils to the site of infection. Macrophage mediators include prostaglandins; leukotrienes; platelet activating factor; cytokines such as interleukin (IL) 1, tumor necrosis factor (TNF) α, IL-6, and IL-12; and chemokines (Tables 1-6 to 1-9).

Although monocytes-macrophages were originally thought to be the major antigen-presenting cells (APCs) of the immune system, it is now clear that cell types called dendritic cells are the most potent and effective APCs in the body (see below). Monocytes-macrophages mediate innate immune effector functions such as destruction of antibody-coated bacteria, tumor cells, or even normal hematopoietic cells in certain types of autoimmune cytopenias. Monocytes-macrophages ingest bacteria or are infected by viruses, and in doing so, they frequently undergo apoptosis.

TABLE 1-6

CYTOKINES AND CYTOKINE RECEPTORS

CYTOKINE

RECEPTOR

CELL SOURCE

CELL TARGET

BIOLOGIC ACTIVITY

^-1α,β

Type I IL-1r, Type II IL-1r

Monocytes/macrophages, B cells, fibroblasts, most epithelial cells including thymic epithelium, endothelial cells

All cells

Upregulated adhesion molecule expression, neutrophil and macrophage emigration, mimics shock, fever, upregulated hepatic acute phase protein production, facilitates hematopoiesis

IL-2

IL-2r α,β, common γ

T cells

T cells, B cells NK cells, monocytes/ macrophages

T cell activation and proliferation, B cell growth, NK cell proliferation and activation, enhanced monocyte/ macrophage cytolytic activity

IL-3

IL-3r,

common β

T cells, NK cells, mast cells

Monocytes/ macrophages, mast cells, eosinophils, bone marrow progenitors

Stimulation of hematopoietic progenitors

IL-4

IL-4r α, common γ

T cells, mast cells, basophils

T cells, B cells, NK cells, monocytes/ macrophages, neutrophils, eosinophils, endothelial cells, fibroblasts

Stimulates TH2 helper T cell differentiation and proliferation. Stimulates B cell Ig class switch to IgG1 and IgE anti-inflammatory action on T cells, monocytes

IL-5

IL-5r α, common γ

T cells, mast cells and eosinophils

Eosinophils, basophils, murine B cells

Regulates eosinophil migration and activation

IL-6

IL-6r, gp130

Monocytes/macrophages, B cells, fibroblasts, most epithelium including thymic epithelium, endothelial cells

T cells, B cells, epithelial cells, hepatocytes, monocytes/ macrophages

Induction of acute phase protein production, T and B cell differentiation and growth, myeloma cell growth, osteoclast growth and activation

IL-7

IL-7r α, common γ

Bone marrow, thymic epithelial cells

T cells, B cells, bone marrow cells

Differentiation of B, T and NK cell precursors, activation of T and NK cells

IL-8

CXCR1,

CXCR2

Monocytes/macrophages, T cells, neutrophils, fibroblasts, endothelial cells, epithelial cells

Neutrophils, T cells, monocytes/ macrophages, endothelial cells, basophils

Induces neutrophil, monocyte and T cell migration, induces neutrophil adherence to endothelial cells, histamine release from basophils, stimulates angiogenesis. Suppresses proliferations of hepatic precursors

IL-9

IL-9r α, common γ

T cells

Bone marrow progenitors, B cells, T cells, mast cells

Induces mast cell proliferation and function, synergizes with IL-4 in IgG and IgE production, T cell growth, activation and differentiation

IL-10

IL-10r

Monocytes/macrophages, T cells, B cells, keratinocytes, mast cells

Monocytes/ macrophages, T cells, B cells, NK cells, mast cells

Inhibits macrophage proinflammatory cytokine production, downregulates cytokine class II antigen and B7-1 and B7-2 expression, inhibits differentiation of TH1, helper T cells, inhibits NK cell function, stimulates mast cell proliferation and function, B cell activation and differentiation

IL-11

IL-11, gp130

Bone marrow stromal cells

Megakaryocytes,

B cells, hepatocytes

Induces megakaryocyte colony formation and maturation, enhances antibody responses, stimulates acute-phase protein production

IL-12 (35 kD and 40 kD subunits)

IL-12r

Activated macrophages, dendritic cells, neutrophils

T cells, NK cells

Induces TH1 helper T cell formation and lymphokine-activated killer cell formation. Increases CD8+ CTL cytolytic activity; TIL-17, ΐγ-IFN

TABLE 1-6

CYTOKINES AND CYTOKINE RECEPTORS

CYTOKINE

RECEPTOR

CELL SOURCE

CELL TARGET

BIOLOGIC ACTIVITY

IL-13

IL-13/IL-4

T cells (TH2)

Monocytes/

macrophages,

B cells, endothelial cells, keratinocytes

Upregulation of VCAM-1 and C-C chemokine expression on endothelial cells, B cell activation and differentiation, inhibits macrophage proinflammatory cytokine production

IL-14

Unknown

T cells

Normal and malignant B cells

Induces B cell proliferation

IL-15

IL-15r α, common y, IL2r β

Monocytes/macrophages, epithelial cells, fibroblasts

T cells, NK cells

T cell activation and proliferation. Promotes angiogenesis, and NK cells

IL-16

CD4

Mast cells, eosinophils, CD8+ T cells, respiratory epithelium

CD4+ T cells, monocytes/ macrophages, eosinophils

Chemoattraction of CD4+ T cells, monocytes, and eosinophils. Inhibits HIV replication. Inhibits T cell activation through CD3/T cell receptor

IL-17

IL17r

CD4+ T cells

Fibroblasts,

endothelium,

epithelium

Enhanced cytokine secretion

IL-18

IL-18r (IL-1R related protein)

Keratinocytes,

macrophages

T cells, B cells, NK cells

Upregulated IFNy production, enhanced NK cell cytotoxicity

IL-21

IL-δγ chain/ IL-21R

CD4 T cells

NK cells

Downregulates NK cell activating molecules, NKG2D/DAP10

IL-23

IL-12Rb1/

IL23R

Macrophages, other cell types

T cells

Opposite effects of IL-12 T(IL-17, Cy-IFN)

IFNα

Type I interferon receptor

All cells

All cells

Anti-viral activity. Stimulates T cell, macrophage, and NK cell activity. Direct anti-tumor effects Upregulates MHC class I antigen expression. Used therapeutically in viral and autoimmune conditions

IFNß

Type I interferon receptor

All cells

All cells

Anti-viral activity. Stimulates T cell, macrophage, and NK cell activity. Direct anti-tumor effects Upregulates MHC class I antigen expression. Used therapeutically in viral and autoimmune conditions

IFNy

Type II interferon receptor

T cells, NK cells

All cells

Regulates macrophage and NK cell activations. Stimulates immunoglobulin secretion by B cells. Induction of class II histocompatibility antigens. TH1 T cell differentiation

TNFα

TNFrI, TNFrII

Monocytes/macrophages, mast cells, basophils, eosinophils, NK cells,

B cells, T cells, keratinocytes, fibroblasts, thymic epithelial cells

All cells except erythrocytes

Fever, anorexia, shock, capillary leak syndrome, enhanced leukocyte cytotoxicity, enhanced NK cell function, acute phase protein synthesis, pro-inflammatory cytokine induction

TNFß

TNFrI, TNFrII

T cells, B cells

All cells except erythrocytes

Cell cytotoxicity, lymph node and spleen development

LT β

LT ßR

T cells

All cells except erythrocytes

Cell cytotoxicity, normal lymph node development

G-CSF

G-CSFr;

gp130

Monocytes/macrophages, fibroblasts, endothelial cells, thymic epithelial cells, stromal cells

Myeloid cells, endothelial cells

Regulates myelopoiesis. Enhances survival and function of neutrophils. Clinical use in reversing neutropenia after cytotoxic chemotherapy

TABLE 1-6

CYTOKINES AND CYTOKINE RECEPTORS

CYTOKINE

RECEPTOR

CELL SOURCE

CELL TARGET

BIOLOGIC ACTIVITY

GM-CSF

GM-CSFr, common β

T cells, monocytes/ macrophages, fibroblasts, endothelial cells, thymic epithelial cells

Monocytes/ macrophages, neutrophils, eosinophils, fibroblasts, endothelial cells

Regulates myelopoiesis. Enhances macrophage bactericidal and tumoricidal activity. Mediator of dendritic cell maturation and function. Upregulates NK cell function. Clinical use in reversing neutropenia after cytotoxic chemotherapy

M-CSF

M-CSFr (c-fms protooncogene)

Fibroblasts, endothelial cells, monocytes/ macrophages, T cells, B cells, epithelial cells including thymic epithelium

Monocytes/

macrophages

Regulates monocyte/macrophage production and function

LIF

LIFr; gp130

Activated T cells, bone marrow stromal cells, thymic epithelium

Megakaryocytes,

monocytes,

hepatocytes,

possibly

lymphocyte

subpopulations

Induces hepatic acute phase protein production. Stimulates macrophage differentiation. Promotes growth of myeloma cells and hematopoietic progenitors. Stimulates thromboiesis

OSM

OSMr; LIFr; gp130

Activated monocytes/ macrophages and T cells, bone marrow stromal cells, some breast carcinoma cell lines, myeloma cells

Neurons, hepato-cytes, monocytes/ macrophages, adipocytes, alveolar epithelial cells, embryonic stem cells, melanocytes, endothelial cells, fibroblasts, myeloma cells

Induces hepatic acute phase protein production. Stimulates macrophage differentiation. Promotes growth of myeloma cells and hematopoietic progenitors. Stimulates thromboiesis. Stimulates growth of Kaposi’s sarcoma cells

SCF

SCFr (c-kit protooncogene)

Bone marrow stromal cells and fibroblasts

Embryonic stem cells, myeloid and lymphoid precursors, mast cells

Stimulates hematopoietic progenitor cell growth, mast cell growth, promotes embryonic stem cell migration

TGFß (3 isoforms)

Type I, II, III TGFß receptor

Most cell types

Most cell types

Downregulates T cell, macrophage and granulocyte responses. Stimulates synthesis of matrix proteins. Stimulates angiogenesis

Lympho-

tactin/

SCM-1

Unknown

NK cells, mast cells, double negative thymocytes, activated CD8+ T cells

T cells, NK cells

Chemoattractant for lymphocytes. Only known chemokine of C class

MCP-1

CCR2

Fibroblasts, smooth muscle cells, activated PBMCs

Monocytes/

macrophages,

NK cells, memory T cells, basophils

Chemoattractant for monocytes, activated memory T cells, and NK cells. Induces granule release from CD8+ T cells and NK cells.

Potent histamine releasing factor for basophiles. Suppresses proliferation of hematopoietic precursors. Regulates monocyte protease production

MCP-2

CCR1, CCR2

Fibroblasts, activated PBMCs

Monocytes/

macrophages,

T cells, eosinophils, basophils, NK cells

Chemoattractant for monocytes, memory and naïve T cells, eosinophils, ?NK cells. Activates basophils and eosinophils. Regulates monocyte protease production

TABLE 1-6

CYTOKINES AND CYTOKINE RECEPTORS

CYTOKINE

RECEPTOR

CELL SOURCE

CELL TARGET

BIOLOGIC ACTIVITY

MCP-3

CCR1, CCR2

Fibroblasts, activated PBMCs

Monocytes/ macrophages, T cells, eosinophils, basophils, NK cells, dendritic cells

Chemoattractant for monocytes, memory and naïve T cells, dendritic cells, eosinophils, ?NK cells. Activates basophils and eosinophils. Regulates monocyte protease production

MCP-4

CCR2, CCR3

Lung, colon, small intestinal epithelial cells, activated endothelial cells

Monocytes/

macrophages,

T cells eosinophils, basophils

Chemoattractant for monocytes, T cells, eosinophils and basophils

Eotaxin

CCR3

Pulmonary epithelial cells, heart

Eosinophils,

basophils

Potent chemoattractant for eosinophils and basophils. Induces allergic airways disease. Acts in concert with IL-5 to activate eosinophils. Antibodies to eotaxin inhibit airway inflammation

TARC

CCR4

Thymus, dendritic cells, activated T cells

T cells, NK cells

Chemoattractant for T and NK cells

MDC

CCR4

Monocytes/macrophages, dendritic cells, thymus

Activated T cells

Chemoattractant for activated T cells. Inhibits infection with T cell tropic HIV

MIP-^

CCR1, CCR5

Monocytes/macrophages, T cells

Monocytes/

macrophages,

T cells, dendritic cells, NK cells, eosinophils, basophils

Chemoattractant for monocytes, T cells, dendritic cells, NK cells, and weak chemoattractant for eosinophils and basophils. Activates NK cell function. Suppresses proliferation of hematopoietic precursors. Necessary for myocarditis associated with coxsackie virus infection. Inhibits infection with monocytotropic HIV

MIP-1 ß

CCR5

Monocytes/ macrophages, T cells

Monocytes/

macrophages,

T cells, NK cells, dendritic cells

Chemoattractant for monocytes, T cells, and NK cells. Activates NK cell function. Inhibits infection with monocytotropic HIV

RANTES

CCR1,

CCR2,

CCR5

Monocytes/macrophages, T cells, fibroblasts, eosinophils

Monocytes/

macrophages,

T cells, NK cells, dendritic cells, eosinophils, basophils

Chemoattractant for monocytes/ macrophages, CD4+ CD45Ro+T cells, CD8+ T cells, NK cells, eosinophils, and basophils. Induces histamine release from basophils. Inhibits infections with monocytotropic HIV

LARC/

MIP-3o/

Exodus-1

CCR6

Dendritic cells, fetal liver cells, activated T cells

T cells, B cells

Chemoattractant for lymphocytes

ELC/

MIP-3ß

CCR7

Thymus, lymph node, appendix

Activated T cells and B cells

Chemoattractant for B and T cells. Receptor upregulated on EBV infected B cells and HSV infected T cells

I-309/

TCA-3

CCR8

Activated T cells

Monocytes/ macrophages, T cells

Chemoattractant for monocytes. Prevents glucocorticoid-induced apoptosis in some T cell lines

SLC/

TCA-4/

Exodus-2

Unknown

Thymic epithelial cells, lymph node, appendix and spleen

T cells

Chemoattractant for T lymphocytes. Inhibits hematopoiesis

DC-CK1/

PARC

Unknown

Dendritic cells in secondary lymphoid tissues

Naïve T cells

May have a role in induction of immune responses

TECK

Unknown

Dendritic cells, thymus, liver, small intestine

T cells, monocytes/ macrophages, dendritic cells

Thymic dendritic cell-derived cytokine, possibly involved in T cell development

TABLE 1-6

CYTOKINES AND CYTOKINE RECEPTORS

CYTOKINE

RECEPTOR

CELL SOURCE

CELL TARGET

BIOLOGIC ACTIVITY

GROα/

MGSA

CXCR2

Activated granulocytes, monocyte/macrophages, and epithelial cells

Neutrophils, epithelial cells, ?endothelial cells

Neutrophil chemoattractant and activator. Mitogenic for some melanoma cell lines. Suppresses proliferation of hematopoietic precursors. Angiogenic activity

GROß/

MIP^

CXCR2

Activated granulocytes and monocyte/ macrophages

Neutrophils and ?endothelial cells

Neutrophil chemoattractant and activator. Angiogenic activity

NAP-2

CXCR2

Platelets

Neutrophils,

basophils

Derived from platelet basic protein. Neutrophil chemoattractant and activator

IP-10

CXCR3

Monocytes/macrophages, T cells, fibroblasts, endothelial cells, epithelial cells

Activated T cells, tumor infiltrating lymphocytes, ?endothelial cells, ?NK cells

IFNy-inducible protein that is a chemoattractant for T cells. Suppresses proliferation of hematopoietic precursors

MIG

CXCR3

Monocytes/macrophages, T cells, fibroblasts

Activated T cells, tumor infiltrating lymphocytes

IFNy-inducible protein that is a chemoattractant for T cells. Suppresses proliferation of hematopoietic precursors

SDF-1

CXCR4

Fibroblasts

T cells, dendritic cells, ?basophils, ?endothelial cells

Low potency, high efficacy T cell chemoattractant. Required for B-lymphocyte development. Prevents infection of CD4+, CXCR4+ cells by T cell tropic HIV

Fractalkine

CX3CR1

Activated endothelial cells

NK cells, T cells, monocytes/ macrophages

Cell surface chemokine/mucin hybrid molecule that functions as a chemoattractant, leukocyte activator and cell adhesion molecule

PF-4

Unknown

Platelets, megakaryocytes

Fibroblasts, endothelial cells

Chemoattractant for fibroblasts. Suppresses proliferation of hematopoietic precursors. Inhibits endothelial cell proliferation and angiogenesis

Note: IL, interleukin; NK, natural killer; TH1 and TH2 helper T cell subsets; Ig, immunoglobulin; CXCR, CXC-type chemokine receptor; B7-1, CD80, B7-2, CD86; PBMC, peripheral blood mononuclear cells; VCAM, vascular cell adhesion molecule; IFN, interferon; MHC, major histocompatibility complex; TNF, tumor necrosis factor; G-CSF, granulocyte colony- stimulating factor; GM-CSF, granulocyte-macrophage CSF; M-CSF, macrophage CSF; HIV, human immunodeficiency virus; LIF, leukemia inhibitory factor; OSM, oncostatin M; SCF, stem cell factor; TGF, transforming growth factor; MCP, monocyte chemotactic protein; CCR, CC-type chemokine receptor; TARC, thymus and activation-regulated chemokine; MDC, macrophage-derived chemokine; MIP, macrophage inflammatory protein; RANTES, regulated on activation, normally T-cell expressed and secreted; LARC, liver and activation-regulated chemokine; EBV, Epstein-Barr virus; ELC, EB11 ligand chemokine (MIP-1 β); HSV, herpes simplex virus; TCA, T-cell activation protein; DC-CK, dendritic cell chemokine; PARC, pulmonary and activation-regulated chemokine; SLC, secondary lymphoid tissue chemokine; TECK, thymus expressed chemokine; GRP, growth-related peptide; MGSA, melanoma growth-stimulating activity; NAP, neutrophil-activating protein; IP-10, IFN-y-inducible protein-10; MIG, monoteine induced by IFN-y; SDF, stromal cell-derived factor; PF, platelet factor.

Macrophages that are “stressed” by intracellular infectious agents are recognized by dendritic cells as infected and apoptotic cells and are phagocytosed by dendritic cells. In this manner, dendritic cells “cross-present” infectious agent antigens of macrophages to T cells. Activated macrophages can also mediate antigen-nonspecific lytic activity and eliminate cell types such as tumor cells in the absence of antibody. This activity is largely mediated by cytokines (i.e^TNF-α and IL-1). Monocytes-macrophages express lineage-specific molecules (e.g., the cell-surface LPS receptor, CD14) as well as surface receptors for a number of molecules, including the Fc region of IgG, activated complement components, and various cytokines (Table 1-6).

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