Cellular Dynamics of Immune Evasion during Leishmania major infection

Abstract

Abstract Infection by Leishmania major generates a strong T cell response, yet clearance is incomplete. Understanding of persistence mechanisms is still lacking, but Leishmania major mediated suppression of antigen presentation mechanisms and the presence of regulatory T cells within the lesion site have been proposed to prevent parasite clearance in vivo. Here, we used a novel TCR transgenic mouse model, where CD4+ T cells recognize an immunodominant peptide derived from Leishmania-glycosomal phosphoenolpyruvate carboxykinase (PEPCK), to visually characterize anti-L. major CD4+ T cell responses both in vitro and in vivo during acute and persistent infection. We confirmed that PEPCK T cells engage in prolonged interactions with infected macrophages, which resulted in high IFNg production. Effector T cell responses were significantly suppressed by PEPCK-specific, but not polyclonal Tregs, indicating that antigen recognition is required for their suppressive activity. High suppressive activity by Tregs correlated with high IL-10 expression and lower IL-12, TNF, and IL-2 production. Finally, adoptive transfer of PEPCK effector T cells into infected mice led to their recruitment into lesion sites, displaying cellular behaviours consistent with antigen recognition. We are currently characterizing whether effector T cell responses are altered in healed lesions, where persistently-infected cells are readily observed. Collectively, our microscopy-based approach will better define effector T cell responses during acute infection, and mechanistic understanding of how Tregs promote parasite persistence within healed skin.