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|Title:||Sphingosine 1-phosphate : regulation of receptor signalling and cross-talk with chemokines|
|Abstract:||The generation and execution of adaptive immune responses require fine control of the migration of lymphocytes in homeostasis and inflammation. Recently it has been shown that certain chemokines and the lipid sphingosine 1-phosphate interact to regulate egress of resting T cells from lymph nodes. As T cells are exposed simultaneously to many chemokines and S1P at other points in their life-cycle, other instances of cross-talk are likely. How S1P receptor signalling changes following T cell activation, and how S1P may modulate cellular responses to chemokines before and after this transition, are important questions. S1P pre-treatment enhanced the chemotaxis of Jurkat T cells towards CXCL12. This was a specific effect as S1P did not affect the amount of cell surface CXCR4 or certain signalling responses downstream of chemokine stimulation. Unexpectedly, this effect was opposite to that observed with primary resting cells, where S1P treatment suppressed migration towards CXCL12. The chemokine-induced phosphorylation of Akt was unaffected, suggesting a PI3Kindependent effect. In contrast, S1P enhanced the migration of activated T cells towards the inflammatory chemokine CXCL10. Using an S1P receptor 1-selective agonist it was shown that receptor signalling in T cells was lost transiently after activation. This was demonstrated, using siRNA, to be partly dependent on the initial upregulation of CD69. The relevance of modulation of S1PR1 signalling was explored further in vivo. The S1P receptor super-agonist FTY720 sequestered activated alloreactive cells in a peripheral lymph node, suggesting that their egress was dependent on S1P receptor signalling. These results show that S1P is a key regulator of T cell migration at three different stages of their life-cycle: before activation, in their response to homeostatic chemokines; following activation, in their ability to egress lymphatic tissue; and finally in the responses of differentiated effector cells to inflammatory chemokines.|
|Appears in Collections:||Institute of Cellular Medicine|
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|Swan 11.pdf||Thesis||7.84 MB||Adobe PDF||View/Open|
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