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).
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.
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).