activation

Activation of cells of the immune system variably induces proliferation, differentiation, production, and maturation. Some activated cells of the immune system are involved in activation (costimulation) of other cell types. Likewise, some activated cells express molecules involved in activation.

▼activating agents : B cell activation : costimulatory agents : costimulatory cells : complement activation pathways : dendritic cell activation : granulocyte activation : lymphocyte activation : macrophage alternative : macrophage classical : markers : mediators : monocyte-macrophage : pDC : phagocyte activation : precursor dendritic cells : signaling/receptors : T cell activation : Tc activation : Th activation▼

Activating agents
_ ● antigen
___ ● pathogens
___ ● pathogen-associated molecular patterns (PAMP)
___ ● danger-associated molecular patterns (DAMP)

Markers
___ ● major histocompatibility complex (MHC) molecules

Costimulatory agents
___ ● CD28
___ ● SLAM (signaling lymphocytic activation molecule), a 70-kDa costimulatory molecule belonging to the Ig superfamily
___ ● ICOS (inducible costimulator) molecules
___ ● TNFR: CD40, CD30, CD27, OX-40, 4-1BB
___ ● negative regulators of costimulation: CTLA-4, PD-1

Costimulatory cells
● helper T cells (Th) for activation of B cells, and APCs for activation of T cells
_ ●Antigen presenting cells display epitope proteins – exogenous antigen or fragmented angtigen from phagocytosed cells – on their surfaces. APCs include:
___ ● phagocytic cells – dendritic cells, macrophages
___ ● B cells (B lymphocytes)

Signaling / receptors
_ ● pattern recognition receptors
_____ ● complement receptors (table)
_____ ● Fc receptors (table)
_____ ● scavenger receptors (table)
_____ ● Toll-like receptors (table)
_ ● TNFR
_ ● B cell receptors (BCR)
___ ● immunoglobulin - antibodies (table)
_ ● T cell receptors (TCR)
_____ ● clusters of differentiation
_____ ● major histocompatibility complex (MHC) molecules

Mediators
_ ● immune cytokines (table)

Phagocytes

Dendritic cells
Dendritic cells and their immature counterparts, Langerhans cells (LC), are highly specialized, professional antigen-presenting cells (APC). Immature dendritic cells are called 'veiled cells' because they display large cytoplasmic 'veils' rather than the long dendritic projections of mature cells. As key regulators of immune responses, dendritic cells (DC) stimulate lymphocytes to perform cell-mediated and humoral immune responses against pathogens and tumor cells.

Immature, precursor dendritic cells (pDC) circulate throughout the body, migrating to lymphocyte rich tissues (such as spleen and lymph nodes) upon stimulating encounter with antigen. The dendritic cells internalize the antigen then externalize (fragmented) antigen that they present to lymphocytes in MHC-peptide complexes, expressing markers that stimulate lymphocyte activation.

Monocyte → macrophage activation
Production of the macrophage lineage from progenitors in the bone marrow is typically controlled by M-CSF, which is constitutively expressed by many cell types. Serum levels of M-CSF and GM-CSF increase in response to invasive stimuli and inflammation, and monocyte numbers increase dramatically. M-CSF-derived macrophages are larger, and have a higher phagocytic capacity, while GM-CSF-derived macrophages are more cytotoxic against TNF-α-resistant tumour targets, express more MHC class II antigen, and constitutively secrete more PGE-2.

Classically activated macrophages are associated with chronic inflammation and tissue injury wherein classically activated macrophages exhibit a Th1-like phenotype, promoting inflammation, destruction of the extracellular matrix (ECM), and apoptosis. Classical macrophage activation proceeds in two stages.
1. IFN-γ-primed stage in which macrophages exhibit enhanced MHC class II expression, antigen presentation, but reduced proliferative capacity. (IFN-α, IFN-β, IL-3, M-CSF, GM-CSF and TNF-α can also prime macrophages for selected functions.)
2. Secondary stimuli operated to fully activate primed macrophages. Diverse agents provide secondary signals (including LPS (CD14), bacteria, yeast glucans, GM-CSF and phorbol esters). Macrophages stimulated for tumoricidal activity secrete IL-1, display decreased MHC class II gene transcription, and are generally poor antigen presenters of antigen.[r]

Alternatively activated macrophages typically resolve inflammation and facilitate wound healing wherein they display a Th2-like phenotype, promoting construction of ECM, cell proliferation, and angiogenesis. Alternative macrophage activation does not require a priming stage and IL-42 and/or IL-1326 can act as sufficient stimuli.[r2]

Granulocyte activation
The hematopoietic cytokines, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have pleiotropic activating effects on mature leukocytes, which can improve leukocyte function, facilitating eradication of microbial infections. G-CSF activates neutrophils, while GM-CSF activates neutrophils, eosinophils, and monocyte/macrophages.

Lymphocytes
B cell activation: naïve B cells → plasma cells
Activation of naïve B cells occurs when a BCR (antibody) encounters and ligates its cognate antigen. B cells are coated in immunoglobulin receptors and are able to recognize intact antigen, which they engulf, digest, and subsequently present in complex with surface MHC class II molecules. The MHC-peptide complex binds CD4 + helper T cells (Th), inducing secretion of cytokines that stimulate B cell proliferation and their differentiation into plasma cells, which secrete specific antibodies that bind with the cognate antigen. These antigen-antibody complexes are subsequently cleared by liver and spleen cells and the classical complement cascade.

T cell activation:
Activation of T cells requires a first signal of TCR engagement, which ensures antigen specificity and MHC restriction of the response. The second signal comprises synergistic costimulatory signaling by professional antigen presenting cells. The costimulatory second signal is necessary to sustain and integrate TCR signaling to stimulate optimal T cell proliferation and differentiation. The level of activation of T cells is closely related to their state of differentiation.

Activation of the resting Tc cell involves two steps: 1) TCR on the CD8+ cell interacts with antigen-class I MHC complex on the surface of a target cell. 2) CD8+ Tc cell is stimulated by cytokines, particularly IL-2, which have been secreted predominantly by activated Th cells. Resting Tc do not express IL-2 receptors until antigen stimulation increases the expression of Tc IL-2 receptors, ensuring that activation is confined to Tc cells that ligate cognate antigen. Activated Tc cells become CTLs.

The first signal for helper T cell (Th) activation is interaction of the TcR-CD3 complex with antigen-MHC class II molecules on the surface of an antigen presenting cell. Stimulation is aided by the CD4 molecule on Th cells, with or without assistance from other accessory molecules, such as CD45, CD28 and CD2. Increased IL-2 secretion by the T cell and an increase in IL-2 receptors on the T cell surface trigger a cascade of biochemical events.



Three pathways are involved in complement activation:
● classical pathway (binding of an antibody to its cognate antigen)
● alternative pathway (relies upon spontaneous conversion of C3 to C3b)
● mannose-binding lectin pathway (MBL -MAPS) (homologous to the classical pathway, but utilizes opsonin, mannan-binding lectin (MBL) and ficolins rather than C1q)

▲ф A activating agents § adaptor protein ~ adhesion molecules ф affinity maturation ♦ AID ф anergy ф antibodies ф antigen ф APCs סּ apoptosis ф autoimmunity B : B cell activation ф B cells ọ blood ọ bone marrow C סּ caspases ф CD סּ cell-cycle control ₪ cellular fate ф cellular response סּ cellular signal transduction סּ chemotaxis ф class-switch recombination ф clonal selection ф complement system : complement activation pathways : costimulatory agents : costimulatory cells ~ cytokines ~ cytokine receptors D סּ death receptor : dendritic cell activation ф dendritic cells ₪ differentiation E סּ ECM F ♦ Fyn G ф gene conversion ọ germinal centers : granulocyte activation ф granulocytes H ф helper T cell ф hematopoiesis ф humoral immunity I ф immune cytokines ф immune response ф immune tolerance ~ immunoglobulins § immunoglobulin isotypes ф inflammatory response ф interferons ф isotype switching L ф leukocytes ф leukocyte adhesion cascade : lymphocyte activation ф lymphocytes ọ lymphoid system ф lymphokines ф lymphoid system M : macrophage alternative : macrophage classical ф macrophages ф MHC ф migration ¤ mitogens ф monocytes : markers : mediators : monocyte-macrophage N § NF-κB P ф pathogens ф pattern-recognition receptors : pDC : phagocyte activation ф phagocyte ф plasma cells : precursor dendritic cells ¤ proliferation R ф receptors S ф secondary antibody diversification ф signaling ¤ signaling molecules : signaling/receptors סּ signal transduction ф somatic hypermutation, somatic mutation ф surface receptors T : T cell activation ф T cells : Tc activation : Th activation ф thymus ọ thymus ф (tolerance) ▲ф


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

▲ Top ▲

tags [Immunology] [activation]

| 0 Guide-Glossary

costimulation

Costimulation involves ligand-receptor interactions at the surfaces of a responder lymphocyte and an "accessory" cell – APCs for activation of T cells, and helper T cells for activation of B cells.

▼activation B : activation T : anergy : CD28 receptor : CD28RE : CDC42 : costimulatory molecules : first/second signals : helper T cell : IL-2 : MAPK cascade : MHC class II : negative regulators : Rac : regulatory mechanisms : Rel-NFkB : Rho GTPases : TCR engagement : TCR threshold reduction : transcription factors : WASP ▼

Activation of B cells occurs when a BCR (antibody) encounters and ligates its cognate antigen. Naïve B cells each have one of millions of distinct surface antigen-specific receptors, yet have not encountered their specific, cognate antigen. With a life-span of only a few days, many B cells die without ever encountering their cognate antigen. In most cases, B-cell activation is dependent upon costimulation by an activated helper T cell that has itself been activated by the same antigen. (click images to enlarge)

Unlike T cells, B cells are coated in immunoglobulin receptors and are able to recognize intact antigen, which they engulf, digest, and subsequently present in complex with surface MHC class II molecules. The MHC-peptide complex binds CD4 + helper T cells (Th), inducing secretion of cytokines that stimulate B cell proliferation and their differentiation into plasma cells, which secrete specific antibodies that bind with the cognate antigen. These antigen-antibody complexes are subsequently cleared by liver and spleen cells and the classical complement cascade.

Activation of T cells requires (1) TCR engagement, which ensures antigen specificity and MHC restriction of the response. However, synergistic signaling by (2) costimulatory molecules is also necessary to sustain and integrate TCR signaling to stimulate optimal T cell proliferation and differentiation.

Delivery of first signal (TCR engagement) in the absence of costimulation by a second signal(s) results in apoptosis or anergy. Anergic T cells neither produce IL-2 nor proliferate upon restimulation. This requirement of naïve T cell activation for delivery of both antigen-specific and costimulatory signals implies that only professional antigen presenting cells can initiate T cell responses.

Activation-regulatory mechanisms:
● increasing TCR avidity (adhesion molecules)
● enhancing recruitment of tyrosine kinases to the TCR complex coreceptors (CD4 and CD8)
● costimulation involving reciprocal and sequential signals between cells

Negative regulators of costimulation include receptors that bind B7 family members:
● CTLA-4
● PD-1

Molecules involved in costimulation include:
1. Disulfide-linked homodimers that bind to distinct members of the B7 family of surface proteins
---● CD28 ↓
---● ICOS (inducible costimulator) molecules
2. Members of the TNF receptor (TNFR) family
---● CD40, the major B cell costimulatory molecule
---● CD30
---● CD27
---● OX-40
---● 4-1BB

The CD28 receptor is involved in the best characterized costimulatory pathway. CD28 is the primary costimulatory molecule for naïve T cells, although CD4+ helper T cells are more dependent than are CD8+ killer T cells on CD28 costimulation. CD28 binds the CD80 (B7-1) and CD86 (B7-2) ligands that are expressed on antigen presenting cells (APCs). CD28 costimulation increases T cell responses in naïve cells by increasing cytokine (mainly IL-2) production, which results from an increase in both cytokine gene transcription and mRNA stabilization.

CD28 signaling involves the activation of the small Rho family GTPases Rac and CDC42, which activate p21-activated kinase. This may link them to the mitogen-activated protein kinase cascades and the subsequent induction of IL-2 synthesis. Rac and CDC42 are also important in CD28-mediated cytoskeletal rearrangements, through the action of the Wiscott-Aldrich syndrome protein (WASP).

CD28 costimulation increases the activity of nuclear transcription factors of the Rel/NFkB family, whose members bind the CD28-responsive element (CD28RE) present in several cytokine gene promoters.

CD28 triggering reduces the number of engaged TCRs necessary to induce cytokine production and cell proliferation. This threshold reduction for T-cell activation is attributed to CD28-induced recruitment of lipid rafts to the immunological synapse, which promotes recruitment of raft-associated kinase and adapter molecules.

▲ activation B : activation T : anergy : CD28 receptor : CD28RE : CDC42 : costimulatory molecules : first/second signals : helper T cell : IL-2 : MHC class II : negative regulators : plasma cells : Rac : regulatory mechanisms : Rel-NFkB : Rho GTPases : TCR engagement : TCR threshold reduction : WASP ▲

Tables  Fc receptors  Immune Cytokines  Immunoglobulins

▲ Top ▲

tags [Immunology][costimulation][activation]

| 0 Guide-Glossary

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