surface receptors

Lymphocytes are coated with surface receptors that participate in the signaling that regulates the adaptive immune response. B lymphocytes carry antibody/ immunoglobulin BCR, while T lymphocytes carry different Ig superfamily TCR.

antigen-MHC complex : BCR : cascade : CD3 : CD4 : CD8 : CD45 : common leukocyte antigen : co-receptor CD4, co-receptor CD8 : cross-linked BCR : enzymes : Fc receptors (FcR) : IgαIgβ : immunoreceptor tyrosine-based activation motifs : intracellular signal : invariant TCR chain : ITAMs : Lck : leukocyte common antigen : lymphocyte receptors : multivalent antigens : phosphorylation : phosphorylated ITAMs : protein kinases : second messengers : signal transduction complex - CD3 : signal transduction molecules : src-family protein tyrosine kinases (PTKs) : Syk : TCR : TCR-CDR3 : TCR diversity : TCR heterodimers : TCR-Ig superfamily : ZAP-70

Activation of signaling requires
lymphocyte receptors, associated with
ITAM-bearing signal transduction molecules, and
adaptor proteins
second messengers

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. Ultimately, gene expression via transcription of mRNA leads to immune activities.

Lymphocyte receptors: BCR and TCR

Heavy chain (H) plus kappa (κ) or lambda (λ) chains.

The surfaces of B cells are coated with one of thousands of distinct Ig superfamily receptors, diversified through VDJ recombination, which bind to their cognate antigen at their antigen-binding site.

Multivalent antigens can cross-link BCR, generating signals of greater amplitude in B cells, and potentially activating the B cells to proliferate and synthesize IgM in the absence of T cell- costimulation. While B cell activation may be possible without antigen presentation, B cells are more efficiently activated by binding of BCR to an array of identical epitopes that are bound to antibody on the Fc receptors (FcR) of macrophages and neutrophils.

Alpha (α) and beta (β) or gamma (γ) and delta (δ) chains

As T cells develop in the thymus, TCR gene segments are recombined to generate diverse, unique TCRs. Only those T cells with a TCR unable to bind self-peptide on self-MHC leave the thymus for the periphery.

Antigen-specific receptors on T cells are not identical to those on B cells (BCRs). The surface receptors of T cells are members of the Ig superfamily, with Ig-like domains. Each T cell is coated with a receptor originating in a single allele, so each receptor binds with a single specificity (CDR3 for antigens and CDR1-2 for MHCs). Clonotypic monoclonal antibodies can recognize TCR idiotypes. Each Ig chain has a variable and a constant region, and CDR of variable regions define the antigen-binding specificity and framework residues.

TCR is a heterodimer composed usually of α and β chains or, in a minority, γ and δ chains. The two chains are disulfide-bonded exterior to the T cell plasma membrane in a short extended stretch of amino acids that resembles the Ig hinge region. TCR, like Ig have very short cytoplasmic tails. Both TCR chains are glycosylated at sites on their V and C regions.

Each TCR has a single CDR3 binding site for antigen, while CDR 1 and CDR 2 bind peptide antigens on MHC. CDR3 is the most variable. Binding to CD4 (on helper T cells) or CD8 (on killer T cells) activates the T cell. Antigen-binding affinity is lower than that of Ig for native (self) antigen, but binding of MHC by the T cell membrane co-receptors CD4 or CD8 increases the binding affinity of the T cell for the antigen-MHC complex.

TCR expressed on the T cell membrane along with a signal transduction complex, CD3, that is called the invariant TCR chain. CD3 molecules on all T cells are formed from identical subunits, which are composed of three dimers: gamma epsilon (γε) or delta epsilon (δε), plus either two zetas (ζζ) or a zeta/eta (ζη) heterodimer. The γ and δ chains of CD3 are not identical to the molecules found in the γd TCR.

CD4 on helper T cells is a monomeric protein with four Ig-like domains, of which the two most distal domains are thought to bind Class II MHC β2 domain. CD8 is a disulfide-linked dimer, where the a and β chains each have one Ig-like domain connected by a long extended region to the transmembrane region. CD8 binds to the α3 region of Class I MHC. The cytoplasmic tails of both CD4 and CD8 associate with a cytoplasmic tyrosine kinase, Lck, to initiate signal transduction.

ф activation ф affinity maturation ф anergy ф antibodies ф antigen ф APCsapoptosis ф B cells ф CDcell-cycle controlcell membranes ф cellular responsecellular signal transduction ф class-switch recombination ф clonal selection ф complement system ф costimulation ~ cytokinesGPCRs ф helper T cell ф immune response ф immune tolerance ф isotype switching ф killer T cells ф leukocytes ф lymphocytes ф lymphokines ф macrophagesMAPKs ф MHC ф monocytes ф neutrophils ф pathogens ф pattern-recognition receptorsphosphatasesphospholipases ~ phospholipase C-gamma ››› phosphorylationphosphotransfer-mediated signaling pathwaysPKCsprotein kinases ~ protein tyrosine kinases (PTKs) ф receptorsreceptor proteinsreceptor-mediated endocytosisreceptor tyrosine kinases ф secondary antibody diversification ~ second messengersserine/threonine kinases ф signaling signaling gradients ¤ signaling moleculessignal transduction ф somatic hypermutation ф T cells ф thymus ф VDJ recombination


Tables  Fc receptors  Immune Cytokines  Immunoglobulins  Cell Adhesion Molecules  Cell signaling  Receptor Tyrosine Kinases (RTKs)  Receptor Signal Transduction  Second Messengers 


Labels: , , ,

. . . since 10/06/06