Control of the protozoan parasite, Leishmania major, is dependent upon establishing a robust T cell response. An early event in the development of an effective T cell response is the expansion (or hypertrophy) of the lymph node draining the site of infection, although the mechanisms involved in this response are not completely understood. Here we show that lymph node hypertrophy following L. major infection in mice is associated with increased recruitment of lymphocytes to the lymph node from the blood, and that CD62L-deficient mice, which are unable to recruit cells to the lymph node, develop a chronic infection with L. major. Injection of L. major activated dendritic cells promoted lymph node hypertrophy, and this correlated with an increase in the expression of CCR7 on dendritic cells, although the upregulation of CCR7 occurred on the bystander (uninfected) dendritic cells rather than those containing parasites. We found that increased CCR7 expression was TLR9 dependent, that TLR9−/− DCs migrated less efficiently to the draining lymph node, and that TLR9−/− mice exhibited a deficit in lymph node expansion following L. major infection, as well as increased susceptibility. Taken together, these results are the first to demonstrate that activation of dendritic cells via TLR9 is essential for the induction of lymph node hypertrophy in leishmaniasis.

Background: MyD88 is a critical element for host resistance to L. major. Results: UNC93B1 mutant and triple TLR3/7/9 knock-out mice are highly susceptible to infection with L. major. Conclusion: Nucleic acid-sensing TLRs are key sensors for Leishmania parasites. Significance: We disclose the mechanism by which L. major initiates IL-12 production and mediates development of Th1 lymphocytes and host resistance to infection.

While C57BL/6 mice infected in the ear with L. major mount a vigorous Th1 response and resolve their lesions, the Th1 response in C57BL/6 mice infected with L. mexicana is more limited, resulting in chronic, non-healing lesions. The aim of this study was to determine if the limited immune response following infection with L. mexicana is related to a deficiency in the ability of monocyte-derived dendritic cells (mo-DCs) to prime a sufficient Th1 response. To address this issue we compared the early immune response following L. mexicana infection with that seen in L. major infected mice. Our data show that fewer monocytes are recruited to the lesions of L. mexicana infected mice as compared to mice infected with L. major. Moreover, monocytes that differentiate into mo-DCs in L. mexicana lesions produced less iNOS and migrated less efficiently to the draining lymph node as compared to those from L. major infected mice. Treatment of L. mexicana infected mice with α-IL-10R antibody resulted in increased recruitment of monocytes to the lesion along with greater production of IFN-γ and iNOS. Additionally, injection of DCs into the ear at the time of infection with L. mexicana also led to a more robust Th1 response. Taken together, these data suggest that during L. mexicana infection reduced recruitment, activation and subsequent migration of monocytes and mo-DCs to the draining lymph nodes may result in the insufficient priming of a Th1 response.

Immunization with Plasmodium yoelii merozoite surface protein (PyMSP)-8 protects mice from lethal malaria but does not prevent infection. Using this merozoite surface protein-based vaccine model, we investigated vaccine- and infection-induced immune responses that contribute to protection. Analysis of prechallenge sera from rPyMSP-8-immunized C57BL/6 and BALB/c mice revealed high and comparable levels of Ag-specific IgG, but differences in isotype profile and specificity for conformational epitopes were noted. As both strains of mice were similarly protected against P. yoelii, we could not correlate vaccine-induced responses with protection. However, passive immunization studies suggested that protection resulted from differing immune responses. Studies with cytokine-deficient mice showed that protection was induced by immunization of C57BL/6 mice only when IL-4 and IFN-γ were both present. In BALB/c mice, the absence of either IL-4 or IFN-γ led to predictable shifts in the IgG isotype profile but did not reduce the magnitude of the Ab response induced by rPyMSP-8 immunization. Immunized IL-4−/− BALB/c mice were solidly protected against P. yoelii. To our surprise, immunized IFN-γ−/− BALB/c mice initially controlled parasite growth but eventually succumbed to infection. Analysis of cytokine production revealed that P. yoelii infection induced two distinct peaks of IFN-γ that correlated with periods of controlled parasite growth in intact, rPyMSP-8-immunized BALB/c mice. Maximal parasite growth occurred during a period of sustained TGF-β production. Combined, the data indicate that induction of protective responses by merozoite surface protein-based vaccines depends on IL-4 and IFN-γ-dependent pathways and that vaccine efficacy is significantly influenced by host responses elicited upon infection.

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