FSU PCB 4233 - Chapter 8 – Lymphocyte Activation

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Chapter 8 Lymphocyte Activation Clustering of membrane receptors o environmental information within the cell is propagated within the cell via plasma membrane receptors o many plasma membrane receptors are protein kinases o stimiluation of the receptors results in phosphorylation with receptors in o B and T cells are associated with molecules called ITAMS that attract these contact with the cytoplasm molecules o ITAMS immmunoreceptor tyrosine based activation motifs T cell receptor TCR CD3 B cell receptor BCR Ig complex chain and chain o ITAMS enable motifs to interact with adaptor proteins Immunological synapse signal routed through the TCR complex to increase affinity of LFA and ICAM 1 accessory molecules when a T cell encounters an Antigen presenting cell APC o Activation of GTPase Rap1 contributes to rapid increase of adhesiveness Two signals are required for the activation of a Accomplished through antigen association with MHC class II on the surface of a mature DC cell na ve helper T cell o Stimulation of the TCR by MHC peptide through receptor CD3 complex o Co stimulatory signal from DC by B7 family ligands on CD28 receptor on o The two stimuli activate RNA synthesis and G1 phase of division o Immature DC cells incapable of activating T cells o Inflammatory cytokines able to facilitate this maturation also PAMP or the T cell cycle DAMP anergic unresponsive to any further stimulation by antigen Activated T cells proliferate in response to 1 signal Protein Tyrosine phosphorylation Early event in T cell signaling The MHC receptor complex recruits CD4 or CD8 coreceptors to enhance interaction with TCR CD4 and CD8 are associated with Lck a protein tyrosine kinase that can phosphorylate ITAMS within the TCR chain mentioned earlier Phosphorylation of the chain recruits another protein tyrosine kinase ZAP 70 ZAP 70 then phosphorylates adaptor proteins LAT and SLP76 o The adaptor proteins then instigate further signaling cascades later on LAT then recruits GADS which is associated with SLP76 and induces cytoskeletal rearrangements BREAKDOWN Initial PTK phosphorylation Recruitment of CD4 CD8 by MHC association with Lck phosphorylation of chain recruitment of ZAP 70 phosphorylation of LAT and SLP76 recruitment of GADS cell shape changes cytoskeleton rearrangement Downstream Signaling Cascades Ras and MAPK Pathways PTK phosphorylation triggers downstream pathways through activation of the GRB2 SOS complex phosphorylation of LAT by ZAP 70 The GRB2 SOS complex promotes the exchange of GDP and GTP which stimulates the RAS activation Phosphatidylinositol Pathway ZAP70 also stimulates recruitment of the 1 isoform of phosphate C this propagates the cascade further This activation hydrolyzes membrane phospholipid phatidylinosiol biphosphate PIP2 INTO TWO THINGS o Diaclglyercol DAG o Inositol triphosphate IP3 IP3 triggers he influx of Ca2 into the cell Consequences of influx o Activation of protein kinase C PKC o Works with calmodulin to increase activity of calcineurin These promote transcription factor required for IL 2 production BREAKDOWN ZAP70 phosphate C PIP2 hydrolysis IP3 activation Ca2 influx PKC calmodulin calcineurin transcription factor Under calcineurin NFAT becomes dephosphorylated The NFAT complex binds to IL 2 regulatory sites which then egulate T cell IL 2 Transcription Control activation CD28 Blocks Apoptosis When CD28 is stimlued a kinase called PI3K propogates signling pathways which can affect cell survival metabolism and protein synthesis Acivation of PI3K also suppresses apoptosis o Downstream a PkB Akt kinase regulates the expression of the ani apoptotic protein Bcl xL Bcl xl inhibits activation of induced cell death CD28 kinase also phosphorylates SLP 76 which recruits Vav which is essential for essential proliferation responses IL 2 production and calcium signaling Research indicates that CD28 costimulation allows to cross thresholds that are no achievable through TCR ligation alone starting a car engine in the cold Also minimizes response to self antigens Downregulation of T cell response Cytotoxic T lymphocyte antigen 4 CTLA 4 binds B7 in an inhibitory fashion o Terminates T cell signaling o Unregulated 3 hours after TCR CD28 activation Has 10 20 times higher affinity for B7 and can beat out CD28 Deficiency in CTLA 4 results in organ destruction and issue infiltration by T for binding cells in mice Induced Cell Death o Expression of membrane FAS CD95 with endogenous inhibitor FLIP Fas receptors insensitive to stimulation due o FLIP Experienced T cells become sensitive to stimulation of Fas receptors due to loss of FLIP over time Stimulation results in apoptosis Immunological Synapse 1 100 000 cells are capable of responding to the MHC peptide complex o Need to be able to efficientl recognize the correct combination of MHC peptide o In continual motion within the lymph node Speed 5000 DC s in 1 hour As few as 10 peptides necessary to begin an immunological synapse with a peptide MHC complex combination Phases of the peptide MHC combination search by lymph node o Phase I seeking phase rapid movement o Phase II stable T cell DC interaction 12 hours IL 2 production o Phase III T cell division and lymph node exit rapid movement 100 MHC peptide complexes can down regulate as many as 18 000 TCRs Immunological synapse between the T cell and the DC has a bull s eye pattern o Called cSMAC central supramolecular activation complex TCR peptide MHC cluster This is surrounded by an outer ring of integrin LFA 1 interacting with ICAM 1 VERY IMPORTANT FOR SNYNAPSE They tether opposing cells to facilitate TCR and peptide MHC interaction Generation of synapse only occurs after initial TCR threshold triggering has been achieved B cells Respond to 3 Types o Antigen Certain types of Antigen can promote B cell activation without T cells o Low affinity o Do not undergo class switching or somatic hypermutation o Provide rapid protection from microorganisms 1 Type 1 Thymus Independent I Activate B cell pool polyclonally No reference to antigen specificity Bind surface molecules like TLR s toll like receptors B cell population with Ig receptors at low concentrations High local population drives activation process 2 Type 2 Thymus Independent II Simulate B cells directly Persist on follicular DC cell surface Bind to antigen specific T cells through attachment to complementary Ig receptors extensive crosslinking of BCRs Both types produce low affinity IgM responses and poor memory 3 Type 3


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FSU PCB 4233 - Chapter 8 – Lymphocyte Activation

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