Inwald, D.P.; (2004) The role of platelet CD40L in inflammation. Doctoral thesis , University of London.

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Abstract

CD40L is a membrane protein belonging to the tumour necrosis factor family, originally found on activated T cells. The CD40L-CD40 interaction is of critical importance in the adaptive immune response, in innate immunity and in inflammation. Recently, activated platelets have been found to express CD40L. Platelets can stimulate endothelial cells via a CD40L-CD40 interaction to upregulate adhesion molecule expression, tissue factor expression and cytokine production. The aim of this project was to investigate the role of platelet CD40L in inflammation, focusing particularly on the platelet-monocyte interaction. A novel assay using thrombin receptor agonist peptide (TRAP) was used to confirm the existence of CD40L on human platelets in whole blood. Using this assay it was demonstrated that resting platelets do not express CD40L. However, CD40L expression occurred within minutes of stimulation with TRAP, with the same kinetics as CD62P expression, suggesting that platelet CD40L is stored, pre-synthesised, in the platelet a-granule. Platelets adhered to both circulating monocytes and the monocytoid cell line THP-1 in a P-selectin dependent manner following stimulation with TRAP. Confirmation of the importance of P-selectin in this interaction came from experiments using blocking antibodies and also from experiments using blood from patients with naturally occurring knockouts of platelet and monocyte adhesion molecules. Platelet CD40L did not induce monocyte cytokine production. During the course of the investigation, it became clear that platelets themselves became activated in response to CD40L. Further experiments demonstrated that platelets constitutively express functional CD40 and that stimulation of platelets with CD40L causes the platelet release reaction to occur. These findings have important implications in the understanding of the biology of human platelets in both health and disease.

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