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