In a previous work, we demonstrated that the induction of arginase I favored the replication of Leishmania inside macrophages. Now we have analyzed the differential expression of this enzyme in the mouse model of L. major infection. Ours results show that arginase I is induced in both susceptible and resistant mice during the development of the disease. However, in BALB/c-infected tissues, the induction of this protein parallels the time of infection, while in C57BL/6 mice, the enzyme is upregulated only during footpad swelling. The induction of the host arginase in both strains is mediated by the balance between interleukin-4 (IL-4) and IL-12 and opposite to nitric oxide synthase II expression. Moreover, inhibition of arginase reduces the number of parasites and delays disease outcome in BALB/c mice, while treatment with L-ornithine increases the susceptibility of C57BL/6 mice. Therefore, arginase I induction could be considered a marker of disease in leishmaniasis.

Stem-like" TCF1 + CD8 + T cells (T SL ) are necessary for long-term maintenance of T cell responses and the efficacy of immunotherapy but, as tumors contain signals that should drive T-cell terminal-differentiation, how these cells are maintained in tumors remains unclear. In this study, we found that a small number of TCF1 + tumor-specific CD8 + T cells were present in lung tumors throughout their development. Yet, most intratumoral T cells differentiated as tumors progressed, corresponding with an immunologic shift in the tumor microenvironment (TME) from "hot" (T cell-inflamed) to "cold" (non-T cell-inflamed). By contrast, most tumor-specific CD8 + T cells in tumor-draining lymph nodes (dLNs) had functions and gene expression signatures similar to T SL from chronic LCMV infection, and this population was stable over time, despite the changes in the TME. dLN T cells were the developmental precursors of, and were clonally related to, their more differentiated intratumoral counterparts. Our data support the hypothesis that dLN T cells are the developmental precursors of the TCF1 + T cells in tumors which are maintained by continuous migration. Finally, CD8 + T cells similar to T SL were also present in LNs from lung adenocarcinoma patients, suggesting a similar model may be relevant in human disease. Thus, we propose that the dLN T SL reservoir has a critical function in sustaining antitumor T cells during tumor development and protecting them from the terminal differentiation that occurs in the TME.

No abstract

Canine leishmaniosis is a zoonotic disease caused by Leishmania infantum. Extensive research is currently ongoing to develop safe and effective vaccines to protect from disease development. The European Commission has granted a marketing authorization for LetiFend®, a new vaccine containing recombinant Protein Q. The efficacy of LetiFend® vaccination in a large-scale dog population of both sexes, different breeds and ages in endemic areas is reported in this multicenter, randomized, double-blind, placebo-controlled field trial. Dogs (n = 549) living in France and Spain were randomly selected to receive a single subcutaneous dose of LetiFend® or placebo per year, and were naturally exposed to two L. infantum transmission seasons. Clinical examinations, blood and lymphoid organ sampling to evaluate serological, parasitological and disease status of the dogs were performed at different time points during the study. LetiFend® was very well tolerated and clearly reduced the incidence of clinical signs related to leishmaniosis. The number of confirmed cases of leishmaniosis was statistically significantly lower in the vaccine group. The number of dogs with parasites was close to be significantly reduced in the vaccine group (p = 0.0564). Re-vaccination of seropositive dogs demonstrated to be safe and not to worsen the course of the disease. The likelihood that a dog vaccinated with LetiFend® develops a confirmed case or clinical signs of leishmaniosis in areas with high pressure is, respectively, 5 and 9.8 time less than that for an unvaccinated dog. Thus, the overall efficacy of the LetiFend® vaccine in the prevention of confirmed cases of leishmaniosis in endemic areas with high disease pressure was shown to be 72%. In conclusion, this field trial demonstrates that LetiFend® is a novel, safe and effective vaccine for the active immunization of non-infected dogs from 6 months of age in reducing the risk of developing clinical leishmaniosis after natural infection with Leishmania infantum.

Inducible expression of neoantigens in mice would enable the study of endogenous antigen-specific naïve T cell responses in disease and infection, but has been difficult to generate because leaky antigen expression in the thymus results in central T cell tolerance. Here, we developed iNversion INduced Joined neoAntigen (NINJA), using RNA splicing, DNA recombination, and three levels of regulation to prevent leakiness and allow tight control over neoantigen expression. We apply NINJA to create tumor cell lines with inducible neoantigen expression, which could be used to study anti-tumor immunity. We also show that the genetic regulation in NINJA mice bypasses central and peripheral tolerance mechanisms and allows for robust endogenous CD8 and CD4 T cells responses upon neoantigen induction in peripheral tissues. NINJA will enable studies of how T cells respond to defined neoantigens in the context of peripheral tolerance, transplantation, autoimmune diseases, and cancer.