Protective CD4+ Th1 cell-mediated immunity is reliant upon execution of effector function prior to the establishment of the pathogen niche

Intracellular infection with the parasite Leishmania major features a state of concomitant immunity in which CD4+ T helper 1 (Th1) cell-mediated immunity against reinfection coincides with a chronic but sub-clinical primary infection. In this setting, the rapidity of the Th1 response at a secondary site of challenge in the skin represents the best correlate of parasite elimination and has been associated with a reversal in Leishmania-mediated modulation of monocytic host cells. Remarkably, the degree to which Th1 cells are absolutely reliant upon the time at which they interact with infected monocytes to mediate their protective effect has not been defined. In the present work, we report that CXCR3-dependent recruitment of Ly6C+ Th1 effector (Th1EFF) cells is indispensable for concomitant immunity and acute (
Author summary Ongoing chronic infection with the intracellular parasite Leishmania major results in robust protective immunity at sites of secondary challenge. However, translation of our understanding of this protective response into an efficient vaccine has remained elusive. This is due, at least in part, to the fact that primary chronic infection maintains multiple effector and memory subsets of lymphocytes, making it difficult to determine the relative importance of any single subset and their functional properties, including the time at which they mediate their effector function. Employing parabiosis, adoptive transfer, and in-vivo blockade of effector functions followed by analysis by intravital microscopy and flow cytometry, we find that the acute availability of circulating CD4+ T helper 1 effector cells (Th1EFF) at the time of secondary challenge is critical for the Th1 immune response to prevent L. major-mediated immunomodulation of host phagocytes and mediate protective immunity. Therefore, the present lack of effective Th1-mediated vaccines that target CD4+ memory T cell generation may be because protective Th1 immunity relies on preactivated Th1EFF cells and IFN-γ availability prior to the establishment of a pathogen niche, which occurs before these memory T cells acquire effector function. To the best of our knowledge, our observations are the first to formally demonstrate the degree to which Th1EFF cells are reliant on the time at which they interact with infected phagocytes to mediate protection and have significant implications for vaccine strategies against phagosomal infections such as Leishmania spp., Mycobacterium tuberculosis, Salmonella enterica, and Crytococcus spp..