Although dendritic cells (DCs) are adept initiators of CD4+ T cell responses, their fundamental importance in this regard in Th2 settings remains to be demonstrated. We have used CD11c–diphtheria toxin (DTx) receptor mice to deplete CD11c+ cells during the priming stage of the CD4+ Th2 response against the parasitic helminth Schistosoma mansoni. DTx treatment significantly depleted CD11c+ DCs from all tissues tested, with 70–80% efficacy. Even this incomplete depletion resulted in dramatically impaired CD4+ T cell production of Th2 cytokines, altering the balance of the immune response and causing a shift toward IFN-γ production. In contrast, basophil depletion using Mar-1 antibody had no measurable effect on Th2 induction in this system. These data underline the vital role that CD11c+ antigen-presenting cells can play in orchestrating Th2 development against helminth infection in vivo, a response that is ordinarily balanced so as to prevent the potentially damaging production of inflammatory cytokines.

Dendritic cells (DC) are known to support the activation of natural killer (NK) cells. However, little is known about the role for DC in NK-cell homeostasis. In order to investigate this question, a novel bacterial artificial chromosome transgenic mouse model was generated in which the diphtheria toxin receptor is expressed under the CD11c promoter. In these mice efficient DC depletion can be achieved over prolonged periods of time by multiple injections of diphtheria toxin. We show here that NK cells require DC for full acquisition of effector function in vivo in response to the bacterial-derived TLR ligand CpG. Importantly, DC were found to play an instrumental role for maintaining normal homeostasis of NK cells. This is achieved by IL-15 production by DC, which supports the homeostatic proliferation of NK cells. . There is much known about the molecular mechanisms of NK-cell functions, but the factors influencing NK-cell numbers are only beginning to be elucidated. Mature NK cells were typically thought to be a terminally differentiated population, with a very limited selfrenewal capacity. However, it was recently shown that a small percentage of NK cells actively proliferate in the steady state, resulting in a half life of the NK-cell population of about 17 days [2]. In addition, like B and T lymphocytes, it was recently found that NK cells can undergo homeostatic proliferation in mice with a reduced NK-cell compartment [2,3]. While IL-7 is essential for the generation and expansion of the T-cell compartment [4][5][6], IL-15 appears to play a dominant role in NK-cell proliferation and survival [2,7]. Mice deficient in IL-15 or IL-15R lack peripheral NK cells [8,9], while mice transgenic for IL-15 show a dramatic increase in NK-cell numbers [10,11]. NK-cell cross talk with dendritic cells (DC) has been described in vitro, resulting in activation of both NK cells and DC [12]. It is known that DC contribute to T-cell homeostasis, especially under lymphopenic conditions [13], but a role for DC in NK-cell homeostasis has not been investigated. In order to study the interactions between DC and NK cells in vivo we utilize here a new bacterial artificial chromosome (BAC) transgenic CD11c.DTR mouse model, designated CD11c.DOG, which allows effective depletion of DC over prolonged periods of time without non-specific cytotoxicity. Using this model, we show that DC are required for NK-cell activation in vivo in response to TLR ligands. SHORT COMMUNICATIONÃ These authors contributed equally to this study. Correspondence: Dr. Natalio Garbi e-mail: n. 2776Importantly, we observe a previously unrecognized role for DC in optimal homeostatic proliferation of NK cells in lymphopenic conditions. In this process, DC-derived IL-15 appears to play an important role. Our data indicate that not only T lymphocytes, but also NK cells require DC for homeostatic proliferation. ResultsCD11c.DOG mice allow long-term ablation of DC in vivo without toxicity effects In order to study the effect of in vivo interaction between DC and NK cell...

Foxp3+CD4+ regulatory T cells (Tregs) are crucial in maintaining self-tolerance and limiting immune responses to pathogens. Shifting the sensitive balance between Tregs and effector T cells requires extensive knowledge of the homeostatic properties of the different T cell populations. For the investigation of Treg homeostatic expansion, we introduce in this study novel BAC transgenic mice, designated Foxp3.LuciDTR, coexpressing enhanced GFP, luciferase for bioluminescence imaging of Tregs, and the diphtheria toxin receptor (DTR) for specific ablation of Tregs. Of several founder lines, Foxp3.LuciDTR-4 mice displayed ∼95% Treg depletion following injection of DT, resulting in activation of conventional CD4+ T cells, probably due to lack of control by Tregs. In contrast, Foxp3.LuciDTR-3 mice displayed only ∼70% Treg depletion without concomitant activation of CD4+ T cells and represented, therefore, a suitable model to study Treg homeostasis in an environment where other T cell populations were not altered. After depletion, the Treg compartment recovered to its original size in ∼2 wk. This recovery was mediated in a thymus-independent fashion by homeostatic proliferation of the surviving, nondepleted Tregs. The proliferating Tregs acquired an activated phenotype and maintained their suppressive capacity. Studies involving DT-mediated depletion of dendritic cells in CD11c.DOG mice showed that dendritic cells were required for optimal Treg homeostasis. In addition, IL-2 was identified as an essential factor for homeostatic recovery of the Treg compartment. These results show that Treg homeostasis is specifically regulated by the size of the Treg compartment and is independent of proliferation of conventional T cells.