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, which 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. [Display omitted] •Th1-Th2 cross-regulation impacts early Leishmania skin infection via monocyte recruitment•STAT6 reduces monocyte recruitment via IFN-γ but controls phagocyte activation via IL-10•Infected monocytes attain an alternatively activated PDL2+phenotype in a Th1 environment•Th2 immunity does not facilitate pathogen replication on a per cell basis Carneiro et al. show during early Leishmania infection of the skin, Th1/Th2 cross-regulationinitially controls the size of the permissive host cell reservoir, while influencing phagocyte activation. The parasite takes advantage of Th1-dependent monocyte recruitment to establish a replication niche and does not require Th2 immunity to enhance intracellular replication.