Lymph Node Hypertrophy following Leishmania major Infection Is Dependent on TLR9

Abstract

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.

Role of Toll-Like Receptor 9 Signaling in Experimental Leishmania braziliensis Infection

“…DC activation by different Leishmania species (L. major and L. infantum) was reported to be TLR9 dependent. L. braziliensis was also shown to induce IL-12 release by DCs in a TLR9-dependent manner (23,25,30,31). However, L. braziliensis strains can harbor Leishmania RNA virus (LRV1) (45), and the presence of LRV1 could influence the immune response, as was shown in L. guyanensis infection (37).…”

“…In humans, L. braziliensis infection has been associated with the presence of enlarged dLNs that harbor parasites, and this lymphadenopathy occurs prior to lesion development (46,47). The increased levels of IFN-␥ at the site of infection and in the dLNs suggested that cell migration to the dLNs is normal in TLR9 Ϫ/Ϫ mice infected with L. braziliensis, which is in contrast to findings for L. major-infected TLR9 Ϫ/Ϫ mice, which exhibit dLN hypotrophy (31). We therefore determined if the increased susceptibility in L. braziliensis-inoculated TLR9 Ϫ/Ϫ mice was associated with altered dLN expansion.…”

“…Furthermore, recent evidence suggests that TLR9-dependent DC activation is critical for resistance against L. major infection (23,30,31). TLR9 Ϫ/Ϫ mice inoculated with L. major displayed temporarily elevated Th2 cytokines; susceptibility in TLR9 Ϫ/Ϫ mice was associated with either an intact or defective Th1 response, depending on the study (25,30,31). In addition, the presence of TLR9 was shown to be essential for the activation of classical DCs (cDCs), plasmacytoid DCs (pDCs), and NK cells in response to L. infantum as well as for the stimulation of cDCs and pDCs by L. braziliensis promastigotes (23).…”

“…For example, C57BL/6 mice deficient in the TLR adaptor molecule, myeloid differentiation factor 88 (MyD88), inoculated with L. major developed transiently larger lesions than did wild-type (WT) mice and exhibited a Th2 response with increased levels of IL-4 in parallel with a decrease in the concurrent Th1 cell response characterized by lower levels of IFN-␥ (26)(27)(28)(29). Furthermore, recent evidence suggests that TLR9-dependent DC activation is critical for resistance against L. major infection (23,30,31). TLR9 Ϫ/Ϫ mice inoculated with L. major displayed temporarily elevated Th2 cytokines; susceptibility in TLR9 Ϫ/Ϫ mice was associated with either an intact or defective Th1 response, depending on the study (25,30,31).…”

Critical role of Toll-like receptor signaling in NK cell activation

“…Overall, during the virus infection, TLR2/9 stimulation can mediate NK recruitment directly via the production of chemokines, as well as enhance the CD69 expression and cytokine secretion. Just during the cutaneous leishmaniasis challenge, NK cells represent an important source for early IFN-, and TLR9 is essential for the induction of NK cell-related IFN- secretion and cytotoxicity during the innate phase of Leishmania (L.) major infection, because lymph node (LN) NK cells from TLR9 -/-mice acquired no cytolytic activity after stimulation with L. major [66]. Further study showed that activation of DCs via TLR9 was essential for the induction of hypertrophy in leishmaniasis, due to the crosstalk between NK cells and DCs [67].…”