Cellular dynamics of immune evasion during Leishmania major infection

Despite the generation of a strong T cell response, clearance of Leishmania major is incomplete. Understanding of the persistence mechanisms is lacking, but Leishmania major driven induction of the immunosuppressive microenvironment through recruitment of regulatory T cells has been proposed to prevent parasite clearance in vivo. In the presented study, we used a novel TCR transgenic mouse model, where CD4+ T cells recognize an immunodominant peptide derived from Leishmania-glycosomal phosphoenolpyruvate carboxykinase (PEPCK), to visualize the dynamics of anti-L. major CD4+ T cell responses and to characterize mechanisms which restrain their effector function. We show that macrophage:T cell interaction dynamics were prolonged upon antigen recognition. This leads to a production of high levels of IFNγ and can be significantly suppressed by PEPCK-specific Tregs in vitro, as compared to polyclonal Treg controls. Treg antigen activation leads to a substantial increase in IL-10 levels, while decreasing IL-12, TNF, and IL-2 production. Intravital microscopy studies characterizing PEPCK-specific CD4+ T cell migration within skin lesions in mice show a significant recruitment of adoptively transferred effector T cells to the lesion site in vivo, displaying behaviours consistent with antigen recognition at early stages, but not at chronic stages. Imaging of infected FoxP3-GFP reporter mice show recruitment of Tregs to the lesion site, where they localize in the lesion, unlike the effectors cells which surround it. Collectively, our findings show for the first time that Leishmania-specific Tregs influence effector CD4+ T cell responses and this could be a mechanism that derives antigen persistence in L. major infection. Research funded by a grant from the GSK-CIHR Partnered Chair Program