immune receptors

The functionality of cells of the immune system is particularly dependent on signal pathways, and the various lymphoid cell types sport an array of receptors.

▼ antigenic determinant : APC costimulation : BCR: complement receptors : cytokines : epitope : FcR : Ig-Fc : IgG : opsonins : pathogen associated molecular patterns : pattern recognition receptors : phagocyte receptors : respiratory burst complement : respiratory burst Fc : : scavenger receptors : TCR : TLR : Toll-like receptors : VDJ recombination ▼

Phagocytes

Phagocytic cells detect infectious agents that bind to a variety of receptors on the phagocytes cell membranes, including:

● Fc receptors (FcR, Ig-Fc) – the constant region (Fc) of IgG on bacterial surfaces can bind to the Fc receptor on phagocytes. Such binding to the Fc receptor requires prior antibody-antigen interaction. The binding of IgG-coated bacteria to phagocytic Fc receptors stimulates both metabolic activity in the phagocytes (respiratory burst) and phagocytic activity. Fc receptors include the clusters of differentiation, CD16 (Fcγ RIII), CD32 (Fcγ RII-A, Fcγ RII-B2, Fcγ RII-B1), and CD64 (Fcγ RI), Fcε RI, and Fcα RI. All FcR are stimulatory except inhibitory Fcγ RII-B1 and B2, which contain immunoreceptor tyrosine based inhibition motifs (ITIMs) in their cytoplasmic tail. Table  Fc receptors

● Complement receptors – Phagocytic cells possess a receptor for the C3b complement opsonins, and binding of C3b-coated bacteria to this receptor stimulates enhanced phagocytosis and the respiratory burst. Table  Complement Receptors.

● Scavenger receptors bind a variety of polyanions on bacterial surfaces, stimulating phagocytosis of the polyanion-coated bacteria. Macrophage scavenger receptors appear to mediate important, conserved functions, so it was likely pattern-recognition receptors that arose early in the evolution of host-defense mechanisms. Table  Scavenger Receptors

● Toll-like receptors are a variety of pattern recognition receptors (PRR) that recognize pathogen associated molecular patterns (PAMP) on infectious agents. Binding of the infectious agents to Toll-like receptors stimulates phagocytosis and the release of inflammatory cytokines (IL-1, TNF-α, IL-6) from the phagocytes. Table  Toll-like Receptors

Tables  Complement Receptors  Fc receptors  Immune Cytokines  Immunoglobulins  Interferons  Scavenger Receptors  Toll-like Receptors .

Lymphocytes

The surfaces of B cells and T cells are coated with thousands of identical copies of different integral membrane receptors (BCRs, TCRs), each capable of binding with a different antigen.

Receptor characteristics
● thousands of copies of integral membrane proteins with unique antigen binding sites
● encoded by genes assembled by VDJ recombination produced without antigen encounter
● the antigen binding site recognizes an antigenic determinant or epitope on the antigen
● binding, by non-covalent forces, is based on complementarity of the surface of the receptor and the surface of the epitope

Binding of receptor to epitope, when accompanied by APC-costimulation, leads to:
● stimulation of the B or T cell to leave the G0 phase and enter the cell cycle
● repeated mitosis generates a clone of cells of identical specificity, each coated with an identical antigen receptor.

Cytokine receptors:
● Hematopoietin family receptors are dimers or trimers with conserved cysteines in their extracellular domains and a conserved Trp-Ser-X-Trp-Ser sequence. The two subunits are i) cytokine-specific, and ii) signal transducing. Examples are receptors for IL-2 through IL-7 and GM-CSF.
___ ● Colony-stimulating factors (CSFs) are glycoprotein molecules that support growth of hematopoietic colonies. Examples are receptors for interleukin 3 (IL-3), G-CSF, GM-CSF, M-CSF.

● Interferon family receptors
Interferons are immune cytokines that are classified, as type I, II, or III, according to the receptors through which they signal. Interferon (INF) family receptors have conserved cysteine residues and include the receptors for IFNα, IFNβ, and IFNγ.

● Tumor Necrosis Factor family receptors possess four extracellular domains. Examples are receptors for TNFα, TNFβ (lymphotoxin β, LT), CD40, CD27, CD30, and Fas.

● Chemokine family receptors have seven transmembrane helices (serpentine, GRCRs) and interact with G protein. This family includes receptors for IL-8, MIP-1, MCP (monocyte chemoattractant protein), and RANTES (regulated upon activation normal T cell expressed and secreted). Chemokine receptors CCR5 and CXCR4 are used by HIV to preferentially enter either macrophages or T cells.

Tables  Complement Receptors  Fc receptors  Immune Cytokines  Immunoglobulins  Interferons  Cell Adhesion Molecules  Cell signaling  Receptor Tyrosine Kinases (RTKs)  Receptor Signal Transduction  Second Messengers  Scavenger Receptors  Toll-like Receptors 

▲ф ф antibodies ф antigen : antigenic determinant ф APCs : APC costimulation : BCR ф BCR ф B cells ф CD ф cellular response ф clonal selection ф complement system : complement receptors ф complement system ф costimulation : cytokines ~ cytokines ф dendritic cells : epitope : FcR  Fc receptors ф granulocytes ф helper T cell ф hematopoiesis ф humoral immunity : Ig-Fc : IgG  Immune Cytokines  Immunoglobulins □□ Immunology ~ immunoglobulins ф inflammatory response ф immune cytokines ф immune response ф lymphocytes ф lymphoid system ф macrophages ф MHC : opsonins ф pathogens : pathogen associated molecular patterns (PAMP) : pattern recognition receptors (PRR) ф pattern-recognition receptors : phagocyte receptors ф phagocyte ф plasma cells : respiratory burst complement ››› respiratory burst : respiratory burst Fc : scavenger receptors ф signaling ф surface receptors : TCR ф TCR ф T cells : TLR : Toll-like receptors : VDJ recombination ▲ф

▲ Top ▲

| 0 Guide-Glossary

immune signaling

In cells of the immune system, signaling leads to activation of cell-type specific immune activities. Ligand interaction with receptors on the surface of cells of the immune system triggers intracellular signal transduction directly or through association with assistant signal transduction molecules (CD3, IgαIgβ, etc.).

Cytokines are secreted by immune cells in response to cellular signaling, and bind to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter cellular activity (gene expression). Interleukins comprise the largest class of cytokines, and are manufactured by one leukocyte to act on other leukocytes as signaling ligands. Cytokines are often produced in cascades.
Cytokine receptors:
● Hematopoietin family receptors
___ ● Colony-stimulating factors (CSFs)
● Interferon family receptors
● Tumor Necrosis Factor family receptors
● Chemokine family receptors

Phagocytic cells of the innate immune response employ:
● Fc receptors (FcR, Ig-Fc)
● Complement receptors
● Scavenger receptors
● Toll-like receptors
__ ● adaptor proteins with TIR domains

Activation of lymphocytes signaling of the adaptive immune response requires:
● lymphocyte receptors, associated with
● ITAM-bearing signal transduction molecules, and
● CD45
● adaptor proteins
● second messengers

Immune signaling serves a variety of functions:
● Pre-peripheral-antigen binding
_ ● apoptotic deletion of cells bearing receptors against self-peptides
● Post-peripheral-antigen binding
_ ● activation of immune and inflammatory response activities
__ ● secretion of immune mediator molecules – acute phase components, antibodies, ingestion, disgestion, externalization, and presentation of fragmented antigen (epitope peptide), complement components, cytokines, eicosanoids (prostaglandins and leukotrienes), kinins
__ ● production of inhibitory molecules, such as IκB that regulate immune activity
__ ● surface expression of cell-type specific markers and receptors
__ ● expression of surface receptors fine-tuned by somatic hypermutation
__ ● activation of clonal expansion by entry into cell cycle and proliferation
__ ● activation of cellular differentiation from precursor to committed cell lines
__ ● activation of cellular maturation from cell line to specialized cells
__ ● cellular survival responses
__ ● chemotaxis, migration, and leukocyte adhesion cascade

Signaling in the innate immune response :

Pattern recognition receptors (PRR) are a class of innate immune response-expressed proteins that respond to pathogen-associated molecular patterns (PAMP) and endogenous stress signals termed danger-associated molecular patterns (DAMP). The evolutionarily more recent adaptive immune response employs diverse surface receptors that display decremental binding affinities for epitope stimuli.

Pattern recognition receptors include:
● Membrane-associated PRR
_____ ● Toll-like receptors (TLR) that sense pathogen-associated or damage-associated molecular patterns. In Drosphila, Toll and immunodeficiency (Imd) receptors may link innate and adaptive immune responses (Fig), responding to bacterial and fungal pathogens and activating NF-κB homologs (Dif, dorsal and Relish), thus driving antimicrobial peptide gene expression.[ffta]
● Cytoplasmic PRR
● Secreted PRR, including complement receptors

Toll-like receptors (TLRs) appear to be one of the most ancient, conserved components of the immune system, and are the basic signaling receptors of the innate immune system. TLRs are activated by molecules associated with pathogens (PAMPs) or with injured host cells/tissue (DAMPs). Most identified TLR ligands are either conserved microbial products that signal the presence of an infection, or endogenous ligands resulting from other danger conditions. TLRs trigger signals evoking synthesis and secretion of cytokines and activation of host defenses through NF-κB, MAP kinases, and costimulatory molecules.

The TLR family is characterized by the presence of leucine-rich repeats, which mediate ligand binding, and co-receptors with the Toll/interleukin-1 receptor-like domain (TIR), which mediate interaction with intracellular signaling proteins. To avoid excessive inflammatory responses, TLR signalling must be tightly regulated. MAPK phosphatase 1 (MKP1) is a key negative regulator of Toll-like receptor (TLR)-induced inflammation in vivo. Phosphorylation of MAPK p38 — which is associated with the modulation of cytokine production — is considerably increased and prolonged in the absence of MKP1. [MKP1]
Table  Toll-like Receptors

NF-κBs, Nuclear Factor kappa Bs, are ubiquitous transcription factors involved in responses to cellular stressors such as cytokines, bacterial antigens, and viral antigens. Free NF-κB translocates to the nucleus where it binds to specific κB sequences in DNA, initiating transcription of related genes, including those for immunoreceptors, cytokines, and its own inhibitor, IκB. Inhibitor of kappa B (IκB, IkappaBalpha) inactivates NF-κB by sequestering NF-κB dimers within the cytoplasm. Physiological activities mediated by NF-κB include cellular proliferation, and inflammatory, immune, and cellular survival responses.
[] signaling pathways []

Signaling in the adaptive immune response :

Antigens act as ligands for BCR, while epitope peptide•MHC complexes act as ligands for TCR. Hematopoietic growth factors stimulate cell division in immune and blood cell lines.

Signal transduction molecules:
Because both BCR and TCR have very short cytoplasmic domains, they must associate with invariant signal transduction molecules in order to generate an intracellular signal (IgαIgβ for BCR, CD3 for TCR). The antigen-specific receptors and signal transduction molecules cluster together in the plasma membrane, and signaling is effected by long ITAM-containing cytoplasmic domains on the signal transduction molecules. ITAMs are immunoreceptor tyrosine-based activation motifs that are phosphorylated by src-family protein tyrosine kinase enzymes (PTK). Protein kinases add phosphate groups to tyrosine (or serine or threonine) residues of other proteins, often those of enzymes. Phosphatases remove the phosphate groups, reversing the effects of protein kinases. Phospholipases such as PLC cleave specific ester bonds in phosphoglycerides or glycerophosphatidates, converting the phospholipids into fatty acids and other lipophilic substances. Phospholipase C-γ cleaves the membrane phospholipid, phosphatidylinositol bisphosphate (PIP2) into the signaling molecules, inositol trisphosphate (IP3) and diacylglycerol (DAG).

Phosphorylation can activate or inactivate enzymes, or can create binding sites that lead to increased concentration of cytoplasmic proteins (and hence their accessibilty for phosphorylation). Activation of lymphocytes also requires CD45 (common leukocyte antigen), which is necessory for receptor-mediated activation of lymphocytes.

Phosphorylated ITAMs can bind to other PTKs (Syk for B cells, ZAP-70 for T cells), triggering a cascade of cytoplasmic enzymes or second messengers, such as calcium ions, diacylglycerol, G-proteins, IP3, MAP kinases, PKCs, and transcription factors, such as NF-κB. Ultimately, gene expression via transcription of mRNA leads to immune activities.

Tables  Apoptosis vs Necrosis  Apoptosis  Cell Adhesion Molecules  Cell signaling  Complement Receptors  Cytokines  Eicosanoid Actions  Fc receptors  Immunoglobulins  Interferons  Receptor Tyrosine Kinases (RTKs)  Receptor Signal Transduction  Second Messengers  Scavenger Receptors  Toll-like Receptors

| 0 Guide-Glossary

receptor proteins

Biologically active molecules (ligands) exert their physiological effect by activating or inducing 3D conformational changes in receptor proteins, which participate in signal transduction, cellular signaling, gene regulation, cellular proliferation and differentiation, or regulation of cellular metabolic processes.

Right - click to enlarge - Cartoon representation of a complex between DNA and the ZIF268 protein, containing 3 zinc finger motifs. The coordinating residues of the middle zinc finger are highlighted. Based on the x-ray structure of PDB 1A1L. Color coding: ZIF268: blue; DNA: orange; Zinc ions: green Author: Thomas Splettstoesser Download high-resolution version (1188x1114, 410 KB)

Receptor proteins are located in the cytoplasm, cell membrane, or nuclear membrane.
1. Cytoplasmic receptor proteins include those that respond to steroid hormones. Ligand activated receptors may enter the cell nucleus where they modulate gene expression.
2. Receptors within cell membranes may be peripheral or trans-membrane proteins. Many receptors for hormones and neurotransmission are trans-membrane proteins.
_a. Metabotropic receptors are coupled to G proteins, acting through various secondary pathways involving ion channels, enzymes such as adenylyl (adenylate) cyclases, and phospolipases, or PDZ domains.
_b. Ionotropic receptors are ligand-activated ion channels that permit entry of ions when the central pore is open.

סּ active transport סּ ion channels [] image - receptor proteins [] 3D image steroid receptor - Zn finger Џ animation - receptor protein :

There are more than 1200 individual human plasma membrane receptors in more than 20 families. Examples of receptor proteins/receptors include:
a. Guanine nucleotide-binding protein-coupled receptors (GPCRs) (metabotropic).
b. serine threonine kinases (SerThr Kinase) : TGF-β; MAPK cascade; phosphoinositol kinase-related kinase (PIKK) family - mTOR (FRAP1), ATM, ATR, DNA-PK
c. receptor tyrosine kinases (RTKs) : EGFR, Tie receptors, Eph RTKs,
d. cytokine receptors
e. integrins
f. TNF receptors : FAS

Џ beautiful Flash 8 animation - Inner Life of the Cell, which shows membrane adhesion-signaling, and Interpretation: Inner Life of the Cell Џ

• A • adhesion • C • cell membranes • cellular adhesion molecules • cellular signal transduction • centrioles • chemotaxis • chloroplast • cilia & flagella • communication • concentration gradients • cytokine receptors • cytoplasm • cytoskeleton • E • energy transducers • endoplasmic reticulum • endosomes • exosome • F • flagella & cilia • G • Golgi apparatus • GPCRs • H • hormones • I • ion channels • L • lysosome • M • meiosis • microtubules • mitosis • mitochondrion • N • Nitric Oxide • neurotransmission • neuronal interconnections • nuclear membrane • nuclear pore • P • pinocytosis • proteasome • protein degradation • pumps • R • receptor proteins • receptor-mediated endocytosis • S • second messengers • signaling gradients • signal transduction • spindle • structure • T • transport • two-component systems • U • ubiquitin • V • vacuole • vesicle •

. 7 TM receptors & GPCRs . Toll . NPR . Integrins . LDL receptors & LRP . Notch . Patched Plexins . Roundabout . RPTPs . RTKs . Ser/Thr Kinase receptors . TNF receptors . Cytokine 1 receptors . T-cell receptors . Cytokine 2 receptors . Netrin receptors .

| 0 Guide-Glossary