The proteinase-activated receptor-2 mediates protective immunity in early experimental leishmaniasis.

Resistance to Leishmania (L.) major depends on the development of a L. major-specific Th1 response, while Th2 differentiation results in susceptibility. We previously showed that the early microenvironment of infected skin delivers important signals for T cell differentiation. We found increased expression levels of coagulation factor X (F10 and FX for protein, respectively) 16 h after infection in the skin of resistant mice compared to susceptible mice. Activated FX is a ligand of proteinase-activated receptor-2 (PAR2), a modulator of inflammatory responses. To assess the role of PAR2, we analysed the course of L. major infection in PAR2-deficient (PAR2-/-) mice on a resistant C57BL/6 background. PAR2-/- mice developed significantly larger lesions and harboured more parasites in footpads and draining lymph nodes compared to wild-type mice. In addition, their antigen-specific T cell response was shifted towards Th2. Conversely, early treatment of susceptible BALB/c mice with a PAR2-agonist reduced parasite loads in footpads and spleens and shifted the T cell response towards Th1. This was accompanied by significantly higher expression of the Th1-promoting cytokines IL-6, IL-12, and TNFα in the infected skin. We conclude that PAR2 activation favours Th1-differentiation and resistance in experimental leishmaniasis due to an altered initial microenvironment with increased expression of Th1-promoting cytokines in the infected skin.