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 as 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 analyzed 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 in 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 TNF-α 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.