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BLG 307 (38)
Clare Chua (38)

lymphocyte activation

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BLG 307
Clare Chua

IMMUNOLOGY LYMPHOCYTE ACTIVATION all immune system responses begin with NAÏVE T CELL ACTIVATION features of T-cell activation that are distinct from other receptor-ligand processes requires MHC-presentation small proportion of T cells can respond to ANY antigen many different MHC-peptide combinations are presented by a single APC self-reactivity is a concern Naive T-cell activation causes their DIFFERENTIATION CD8+ cells respond to MHC class I  indicates viral infection (cytosolic protein) activation causes diffentiation into CYTOTOXIC T CELLS (kill infected host cell) CD4+ cells respond to MHC class II  indicates microbial infection (replicating intracellular vesicles) -activation causes differentiation into TH1 or TH2 cells TH1 – inflammatory response (macrophage mediated) TH2 – antigenic response (B-cell mediated) T CELL COSTIMULATION – signal 1 = antigen-MHC signal 2 = antigen independent costimulatory signal (CD28 on T cell an B7 on APC) **ensures that only APC’s can cause T-cell differentiation** **signal 1 without costimulationANERGY** APC’s: DC’s – MOST important activator of T-cells; presents viral antigens (good for innate immunity) Macrophages – present bacterial antigens (scavengers) (B7 inducible by microbial products) B cells (B7 inducible by microbial products (LPS) (good for low level circulating Ag) bind through Ab (Raymond removed a table describing antigen uptake, MHC expression, costimulation, antigen presentation, and location characteristics of B cells, macrophages, and dendritic cells.) NOTE: DIFFERENTIATED, EFFECTOR T CELLS STIMULATED BY SIGNAL ONE ALONE! STAGES OF T- CELL ACTIVATION 1 Stage: T cell encounters antigen/MHC complex on APCupregulate IL-2 and IL2R 2 Stage: T cells proliferate as a result of autocrine growth stimulation by IL-2 and acquire effector functions INITIAL ENCOUNTER WITH APC’s(lymph nodes, Peyer’s Patches, spleen) – SIGNAL 1 1) Adhesion mediated by L-selectin (T) and addressins (CD34 or GlyCAM1 on endothelium) 2)T-cells diapedesis through the endothelial walls mediated by LFA (T) and ICAM (endothelium) 3) Upon APC encounter, binding is first antigen INDEPENDENT Adhesion mediated: CD2 and LFA-1(T) and LFA-3 and ICAM (APC) 4) Antigen-dependent binding involves CD4/CD8 AND TCR to MHC on APC (signal one) -Mediated by ITAM, found within the INVARIANT chain of TCR (cytoplasmic CD3 complex) -ITAM is phosphorylated (by LCK dragged to surface by CD4 or CD8) -SH2 binding domain is exposed. ITAM binds ZAP-70 (protein kinase) (LCK phos. ZAP-70)? -ZAP-70 phos. LAT  TYROSINE kinase cascades activated 5) TCR crosslinking initiates two intracellular signaling cascades PROTEIN KINASE PHOSPHOLYLATES PLC and PROTEINS THAT RECRUIT RAS PATHWAY cascade 1: phospholipase C (PLC) hydrolyzes PIP2 to IP3 and DAG (SEE PAGE 210) -IP3 causes intracellular increase in Ca++ -Ca++ activates CALCINEURIN (phosphatase) -CN dephos. NFAT, exposing an NLS -NFAT can enter nucleus and stim. IL2 txn **CN is a target of immunosuppressive drugs (CsA/FK506)** -DAG activates Protein Kinase C cascade 2: Ras activated **both cascades upregulate IL2 and IL2Rα transcriptionautocrine stimulatory loopcell proliferation** NOTES -Cytoplasmic portion of TCR ζ alone (crosslinking) can trigger phosphorylation, increased Ca+ and IL-2 secretion- -Cytoplasmic tail of the CD3ε alone can also transducer activation signals- -Active signaling component of invariant chain is ITAM (3x in ζ) (2x in η) (once in each CD3 chain) -Each ITAM has a duplicated consensus sequence to bind SH2 domain (assembles signaling machinery) -ITAM couples TCR complex to intracellular tyrosine kinase ZAP-70 -phosphorylation of invariant chains(CD4/CD8 mediated) initiates ITAM binding to ZAP70 -ZAP 70 binds ITAM b/c it has two SH2 domains spaced to engage both pTyrosines on ITAM -simultaneous double binding and conformational change -ZAP 70 expressed in T cells and NK cells. -Mutate ZAP 70STD (selective T cell defect from lack of CD8+ T cells, CD4+ cells don’t proliferate) -loss of kinase activity, fail to produce IL-2 (ZAP-70 essential for TCR mediated signaling) LAT (LINKER FOR ACTIVATION OF T-CELLS) zap 70 substrate couples TCR to activation -HphB MP has multiple phosporylation sites, expressed in thymus, circulating and splnic T cells -associates with Grb2 (activates Ras) and PLC-γ1 (needs two tyrosine residues) -needed to actiave AP-1 and NF-AT transcription factors -restore MAP kinase activity and CA fux by transfecting with JCAM 2 -LA
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