Effector function prior to establishment of the phagosomal pathogen niche is required for protective CD4+ T cell-mediated immunity against Leishmania

Abstract

Abstract Leishmania is an appealing model organism to study CD4+ T cell-mediated protective immunity against phagosomal pathogens which features localized primary and secondary infection sites with defined innate and adaptive responses. Upon secondary challenge of chronic L. major-infected C57Bl/6 mice, rapid CD4+T effector (TEFF) function via IFN-g-mediated activation of infected monocytes is associated with optimal immunity. However, the requirement for immediate effector function has yet to be demonstrated. Thus, we isolated time as a variable in the delivery of CD4+ TEFF effector function. We adoptively transferred (AT) chronic mouse-derived Ly6C+CD4+TEFFs into naïve recipients immediately (D0) or 4 days (D4) post-L. major challenge. In this time window Leishmania establishes an intracellular niche but does not proliferate. At day 21 post-challenge, D4 AT resulted in a total loss of the parasite control mediated by D0 transfer. To address whether parasite niche establishment modulated Th1 TEFF cell recruitment, we employed intravital imaging. Ag-sp T cells were present in the infected dermis at significantly lower numbers following D4 vs D0 transfer at 4 days post-T cell transfer, indicating a recruitment deficit. Rapid CD4+ Th1 effector function was required for circulating Th1 TEFF cells to capitalize on an early recruitment window associated with cxcl9 and cxcl10 expression and to prevent parasite niche establishment through altered cell recruitment, gene expression, and functional capacity of both innate and adaptive immune cells. Thus, acute TEFF cell availability is required to prevent host immunomodulation by Leishmania and is a key consideration for vaccination against phagosomal pathogens reliant on Th1 immunity.