The interface between innate and adaptive immune responses: the role of coagulation proteins

The role of coagulation proteins (CPs) in systems other than haemostasis is now recognised. Many of these cellular effects are through protease activated receptors (PARs). This project investigates how CPs influence the adaptive immune response, firstly through the expression of tissue factor (TF) on DCs; secondly through the action of PARs on dendritic cells (DCs) and T cells; and thirdly by examining the direct effect of anti-thrombin (AT) on DCs. This work identified for the first time a subset of mouse DCs that expresses TF. The form of TF changed from cryptic to pro-coagulant as DCs matured. In addition it was found that blocking TF on immature but not mature DCs enhanced their stimulatory capacity, possibly through PAR-2 signalling. In vivo studies supported this finding and suggest that inhibiting TF breaks T cell tolerance. Thrombin enhanced the T cell response through an effect on DCs but not T cells. Both primary and secondary responses increased but there was no change when stimulated T cells were rechallenged with thrombin-incubated DCs. This mechanism was not through changes in MHCII, co-stimulatory molecules or cytokine production. Although DCs expressed PAR, individual PAR-1 or PAR-4 activation did not affect DC stimulatory capacity. Anti-thrombin was found to reduce T cell activation in vivo. When DCs were treated with AT alone there was no change in T cell response, whereas treatment with AT before LPS led to an increase in IL-4 and IL-10 from T cells suggesting induction of tolerance. Anergy and T cell suppressor assays, however, failed to demonstrate a tolerant phenotype. Overall the findings demonstrate that DCs have the ability to generate and respond to CPs and thus influence the T cell response. This work identifies potential new targets in the innate system which may be used to influence the adaptive immune response.EThOS - Electronic Theses Online ServiceKidney Research UK (KRUK)GBUnited Kingdo