Abstract
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 (<4 days post-infection) Th1EFF cell-phagocyte interactions are critical to prevent the establishment of a permissive pathogen niche, as evidenced by altered recruitment, gene expression and functional capacity of innate and adaptive immune cells at the site of secondary challenge. Surprisingly, provision of Th1EFF cells after establishment of the pathogen niche, even when Th1 cells were provided in large quantities, abrogated protection, Th1EFF cell accumulation and IFN-γ production, and iNOS production by inflammatory monocytes. These findings indicate that protective Th1 immunity is critically dependent on activation of permissive phagocytic host cells by preactivated Th1EFF cells at the time of infection.
Highlights
CD4+ T helper 1 (Th1) cells are critical for protective immunity against the vector transmitted intracellular parasite Leishmania major, which targets dermal phagocytes as host cells for infection and replication resulting in cutaneous leishmaniasis
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
While bone-marrow derived monocytes are essential for parasite control at re-challenge sites [18,19], protection in this model system was not mediated by permanent changes in phagocytic progenitors from mice with a healed primary infection, i.e., innate memory [24], as transfer of bone-marrow (BMT) from chronic mice conferred no protection in naïve, irradiated recipients, a methodology employed by us previously ([34], 2o BMT group in Fig 1N and 1O), and resulted in no change in the frequencies of CD11b+, iNOS+CD11b+ or Ly6C+MHC II+ monocytes relative to intact naïve or naïve transfer controls (Fig 1P), all of which were significantly lower than intact chronic mice that have CD4+ TEFF, T central memory (TCM) and T resident memory (TRM) cells [17,22,23]
Summary
CD4+ T helper 1 (Th1) cells are critical for protective immunity against the vector transmitted intracellular parasite Leishmania major, which targets dermal phagocytes as host cells for infection and replication resulting in cutaneous leishmaniasis. These Th1EFF cells are not derived from memory cells induced to proliferate by secondary challenge, are short-lived in the absence of an ongoing primary infection, can be recruited to the skin in an antigen-independent manner, and are 80% IFN-γ single-producing cells in-vivo [17] At secondary sites this concomitant response is associated with the rapid activation of iNOS+CCR2+ monocytes that facilitate parasite elimination [18,19] as well as heterologous protection against visceral forms of the disease in the spleen and liver caused by L. infantum [20]. Protective CD4+ Th1 effector function must act prior to the establishment of the pathogen niche the delayed recruitment of TCM-derived TEFF cells following clonal expansion in the dLN is either not protective or associated with sub-optimal protection [17,22] These observations suggest Th1 cells must interact with phagocytes at the time of, or shortly after, Leishmania infection in order to mediate efficient protective immunity. Because Th1EFF cells require persisting antigen to be maintained, we suggest that our observations provide the strongest evidence to date that the vaccination strategy most likely to succeed again phagosomal infections is one that maintains circulating Th1EFFs, such as a live-attenuated vaccine [31]
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