Molecular mechanisms governing Fcgamma receptor mediated signal transduction

Cameron, Angus J M (2000) Molecular mechanisms governing Fcgamma receptor mediated signal transduction. PhD thesis, University of Glasgow.

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Receptors for the constant region of immunoglobulin G (FcgammaRs) expressed on myeloid cells play a pivotal role in the clearance of immune complexes and cell activation. In this thesis, the human monoblastic cell line, U937, has been used as a model system to study the coupling of Fcgamma receptors to specific signal transduction events. These cells are known to express both the high affinity receptor, FcgammaRI, and the low affinity activation receptor, FcgammaRIIa. Previous work has shown that the nature of the signalling cascades initiated by FcgammaRI fundamentally changes as U937 cells differentiate from a monocyte to a more macrophage phenotype. This thesis describes mechanisms that underlie this developmental switch. In IFNgamma primed U937 cells, FcgammaRI is coupled to the activation of phospholipase D (PLD). As the subsequent calcium mobilisation is independent of measurable inositol trisphophate production and is not coupled to calcium influx, we examined a potential role for the 5' inositol phosphatase, SHIP, which has been characterised to block both PLC? activation and calcium influx in mast and B-cells. Here, I demonstrate that following immune complex stimulation, SHIP is tyrosine phosphorylated and associates with the adapter protein. Shc, and immune complexes at the plasma membrane. In B-cells and mast cells, SHIP is recruited by the inhibitory Fc receptor, FcgammaRIIb. However, in IFNgamma primed U937 cells, no FcgammaRIIb could be found. Interestingly, FcgammaRIIb expression was induced following differentiation of U937 cells to a more macrophage phenotype using dibutyryl cyclic AMP (dbcAMP). This was surprising as here immune complexes activate PLCgamma and induce calcium influx. In these cells, FcgammaRIIb appears to modulate rather than inhibit immune complex activation. In IFNy primed U937 cells, activation of PLCgamma was coupled to FcgammaRIIa but not to FcgammaRI. The mechanism of this coupling was investigated. I demonstrate that FcgammaRIIa recruits preformed SLP76:PLCgamma complexes to the plasma membrane whereas FcgammaRI does not. I further show that FcgammaRI and FcgammaRIIa induce distinct activation patterns of the MAP kinase cascades. Finally I have demonstrated that the signalling pathway initiated by FcgammaRI depends entirely on the recruited accessory molecule. Thus, in IFNgamma primed cells, FcgammaRJ physically and functionally associates with the gamma-chain. Conversely, in dbcAMP differentiated cells, FcgammaRI no longer uses the gamma-chain but is coupled to PLC? activation by the recruitment of FcgammaRIIa. The gamma-chain in these differentiated cells is preferentially associated with the IgA receptor and appears to define receptor coupling to PLD.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Janet Allen
Keywords: Immunology.
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Supervisor, not known
Date of Award: 2000
Depositing User: Enlighten Team
Unique ID: glathesis:2000-73271
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jun 2019 08:56
Last Modified: 26 Aug 2021 15:16
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