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.