TLR8 on dendritic cells and TLR9 on B cells restrain TLR7-mediated spontaneous autoimmunity in C57BL/6 mice.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with diverse clinical presentations characterized by the presence of autoantibodies to nuclear components. Toll-like receptor (TLR)7, TLR8, and TLR9 sense microbial or endogenous nucleic acids and are implicated in the development of SLE. In mice TLR7-deficiency ameliorates SLE, but TLR8- or TLR9-deficiency exacerbates the disease because of increased TLR7 response. Thus, both TLR8 and TLR9 control TLR7 function, but whether TLR8 and TLR9 act in parallel or in series in the same or different cell types in controlling TLR7-mediated lupus remains unknown. Here, we reveal that double TLR8/9-deficient (TLR8/9(-/-)) mice on the C57BL/6 background showed increased abnormalities characteristic of SLE, including splenomegaly, autoantibody production, frequencies of marginal zone and B1 B cells, and renal pathology compared with single TLR8(-/-) or TLR9(-/-) mice. On the cellular level, TLR8(-/-) and TLR8/9(-/-) dendritic cells were hyperesponsive to TLR7 ligand R848, but TLR9(-/-) cells responded normally. Moreover, B cells from TLR9(-/-) and TLR8/9(-/-) mice were hyperesponsive to R848, but TLR8(-/-) B cells were not. These results reveal that TLR8 and TLR9 have an additive effect on controlling TLR7 function and TLR7-mediated lupus; however, they act on different cell types. TLR8 controls TLR7 function on dendritic cells, and TLR9 restrains TLR7 response on B cells.

Cutaneous Leishmaniasis Vaccination: A Matter of Quality.

There have been exhaustive efforts to develop an efficient vaccine against leishmaniasis. Factors like host and parasite genetic characteristics, virulence, epidemiological scenarios, and, mainly, diverse immune responses triggered by Leishmania species make the achievement of this aim a complex task. It is already clear that the induction of a Th1, pro-inflammatory response, is important in the protection against Leishmania infection. However, many questions must still be answered to fully understand Leishmania immunopathology, especially regarding Leishmania-specific Th1 response induction, regulation, and persistence. A large number of Leishmania antigens able to induce pro-inflammatory response have been selected so far, but none of them demonstrated efficiency in protection assays. A possible explanation is that CD4 T cells display marked heterogeneity at a single-cell level especially regarding the production of Th1-defining cytokines and multifunctionality. It has been established in the literature that Th1 cells undergo a differentiation process, which can generate cells with diverse phenotypes and survival capabilities. Despite that, only a few studies evaluate this heterogenic response and the amount of multifunctional CD4 T cells induced by Leishmania vaccine candidates, missing what can be a crucial point in defining a correlate of protection after vaccination. Moreover, most of the knowledge involving the development of cutaneous leishmaniasis (CL) vaccines comes from the mouse model of infection with Leishmania major, which cannot be fully applied to New World Leishmaniasis. For this reason, the immune response triggered by infection with New World Leishmania species, as well as vaccine candidates, need further studies. In this review, we will reinforce the importance of evaluating the quality of immune response against Leishmania, using a multiparametric analysis in order to understand better this complex host-parasite interaction, discussing the differences in the responses triggered by different New World Leishmania species, as well as the impact on the development of an effective vaccine against CL.