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Title: Molecular mechanisms of immune regulation by the receptors CD5 and CD6
Author: Breuning, Johannes
ISNI:       0000 0004 6497 3610
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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T cells are adaptive immune cells that are essential for initiating and regulating immune responses. T cell activation is triggered by stimulation of the T cell receptor. However, sustained T cell activation requires the function of a variety of coreceptors, among them CD5 and CD6. Both receptors have been shown to have activating and inhibitory functions and modulation of CD6 function is dependent on engagement by its ligand CD166. Costimulatory signalling by CD6 involves a phosphorylation-dependent interaction between the C-terminal Y662 residue and the adaptor protein SLP-76. However, the CD6 cytoplasmic region is one of the longest in the immune system and contains phosphorylated residues which suggests that additional signalling molecules can be recruited. I identified an interaction of CD5 and CD6 with the cytoskeleton via ezrin, radixin and moesin. This interaction has an activating function on Jurkat cell activation and may play a role in receptor localisation. I also identified the adapter protein GADS as a binding partner of the CD6 Y629 residue and found evidence for bivalent binding of the GADS/SLP-76 complex to the CD6 C terminus. Costimulation by CD6 is dependent on the recruitment of this complex and mutant CD6 that cannot recruit it does not provide costimulation and may even be inhibitory in the absence of its ligand. These results suggest a model in which costimulation by CD6 depends on cooperative binding of the GADS/SLP-76 complex to two C-terminal phosphotyrosine residues in the CD6 cytoplasmic region. Binding of this complex to CD6 may enhance long-term signalling by keeping GADS/SLP-76 at the membrane or it may provide an alternative signalling pathway that enhances TCR signalling.
Supervisor: Brown, Marion H. ; Barclay, Neil Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available