Th1/Th2 cross-regulation controls early Leishmania infection in the skin by modulating the size of the permissive monocytic host cell reservoir

The impact of T helper (Th) 1 versus Th2 immunity on intracellular infections is attributed to classical versus alternative activation of macrophages leading to resistance or susceptibility. However, observations in multiple infectious settings demonstrate deficiencies in mediators of Th1/Th2 immunity have paradoxical or no impact. We report that prior to influencing activation, Th1/Th2 immunity first controls the size of the permissive host cell reservoir. During early Leishmania infection of the skin, IFN-γ- or STAT6-mediated changes in phagocyte activation were counteracted by changes in IFN-γ-mediated recruitment of permissive CCR2+ monocytes. Monocytes were required for early parasite expansion and acquired an alternatively activated phenotype despite the Th1 dermal environment required for their recruitment. Surprisingly, STAT6 did not enhance intracellular parasite proliferation, but rather modulated the size and permissiveness of the monocytic host cell reservoir via regulation of IFN-γ and IL-10. These observations expand our understanding of the Th1/Th2 paradigm during infection. C57BL/6 mice were infected with 10^4 Leishmania amazonensis-RFP parasites into the skin. After 2 wks non-infected (RFP-) and infected (RFP+) monocytes were sorted out for genetic expression analysis.n=3 for each control (non-infected monocytes) and experimental group (infected monocytes). The impact of the infection on monocytes were analysed for 254 genes (248 inflammation-related mouse genes + 6 internal reference controls. We performed the multiplex gene expression analysis using the nCounter® Mouse Inflammation v2 Panel from NanoString.