A novel CD11c.DTR transgenic mouse for depletion of dendritic cells reveals their requirement for homeostatic proliferation of natural killer cells

Abstract

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...

In vivo depletion of DC impairs the anti‐tumor effect of agonistic anti‐CD137 mAb

“…Additionally, resistance to the DTx may occur when exposure is extended [56]. Nonetheless, we confirm a drastic reduction of DC throughout our depletion experiments.…”

“…Nonetheless, we confirm a drastic reduction of DC throughout our depletion experiments. A new transgenic mouse with less leaky expression of the DTR has been recently described that permits repeated depletions without need to generate the BM chimeras [56].…”

“…Nonetheless, we confirm a drastic reduction of DC throughout our depletion experiments. A new transgenic mouse with less leaky expression of the DTR has been recently described that permits repeated depletions without need to generate the BM chimeras [56].Indirect evidence for the involvement of DC in CD137-targeted therapies has been provided previously [57,58]. These reports show that artificially eliciting activation/maturation of DC in vivo synergizes with anti-CD137 mAb.…”

Different NK Cell Developmental Events Require Different Levels of IL-15 Trans-Presentation

“…3A), we examined the NK cell response in total splenocyte culture. As LPS-or CpG-activated murine DCs trans-present IL-15 to prime NK cells (26,27,31,32), we first determined whether IL15Ra on splenocytes affects the NK cell response in the absence of microbial stimulation. WT and KO NK cells expressed a similar level of surface NK1.1 before stimulation (Supplemental Table I).…”

Homéostasie des cellulesnatural killer

“…Cette voie dépendante de l'IL-12 est cependant négligeable en présence d'IL-15 : en effet, en l'absence de récepteur à l'IL-12, les cellules NK survivent et prolifèrent de façon tout à fait normale lors d'une infection [17]. Plusieurs articles ont montré que les cellules dendritiques sont également indispensables à la survie des cellules NK matures en périphérie via leur production d'IL-15 [19,20]. Lorsque le nombre de cellules dendritiques est artificiellement augmenté dans les souris (via l'injection de Flt3-ligand [FMS-like tyrosine kinase 3 ligand] par exemple), la population de cellules NK augmente, augmentation qui dépend de la présence d'IL-15 [19].…”