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Keywords:

  • Dendritic cells;
  • Diphtheria toxin;
  • Langerhans cells;
  • Monocytosis;
  • Neutrophilia

Abstract

  1. Top of page
  2. Abstract
  3. Acknowledgements
  4. Conflict of interest
  5. References

Dendritic cells (DCs) play a key role in regulating innate and adaptive immunity. Our understanding of DC biology has benefited from studies in CD11c.DTR and CD11c.DOG mouse models that use the CD11c promoter to express a diphtheria toxin (DT) receptor transgene to inducibly deplete CD11c+ cells. Other models to inducibly deplete specific DC subsets upon administration of DT have also been generated. However, most models suffer from limitations such as depletion of additional cell types or the requirement to be used as radiation chimeras. Moreover, CD11c.DTR and CD11c.DOG mice have recently been reported to display neutrophilia and monocytosis upon DT injection. We discuss here some of the limitations that should be taken into consideration when interpreting results obtained with mouse models of DC ablation.

Dendritic cells (DCs) are antigen-presenting cells with roles in innate and adaptive immune responses. They comprise a heterogeneous group of cells and, therefore, are generally classified into subsets based on (i) select functional attributes, (ii) differences in levels of expression of certain cell-surface markers, and (iii) ontogenetic relationships [1-4]. Broadly speaking, DCs can be subdivided into two main groups: plasmacytoid DCs (pDCs), which utilize Toll-like receptors 7, 8, and 9 to respond rapidly to viruses by producing interferon-α; and conventional DCs (cDCs), which display an exquisite capacity to initiate T-cell responses [1, 4]. cDCs in lymphoid tissues can be further divided into those normally resident at those sites (resident DCs) versus those that have immigrated from elsewhere (migrating DCs) [1-4]. The latter normally reside in nonlymphoid tissues but migrate to the draining lymph nodes via afferent lymphatics in the steady state and, prominently, during inflammation. Both resident and migrating cDCs can be further divided into additional subsets. One such subset is the CD8α-expressing DC that resides in lymphoid organs and its CD103-expressing CD11b counterpart in tissues, both of which are thought to possess a superior capacity to cross-present exogenous antigens to CD8+ T cells [1-4]. Langerhans cells (LCs) represent another well-characterized population of DCs that resides in the skin and can migrate to skin-draining lymph nodes. LCs express high levels of the C-type lectin Langerin and, in contrast to cDCs and pDCs, are radioresistant and, therefore, remain of host origin in chimeric mice reconstituted with syngeneic bone marrow [5].

Our knowledge of DC biology has greatly benefited from the introduction of the CD11c.DTR mouse model (Table 1) a decade ago [6]. This transgenic mouse strain expresses the diphtheria toxin receptor (DTR) under the control of a minimal CD11c promoter, which is active in both pDCs and cDCs. When CD11c.DTR mice are injected with diphtheria toxin (DT), cDCs and, to a lesser extent, pDCs are depleted, allowing for the study of DC-independent immune reactions; however, CD11c.DTR mice die after repeated DT injections, probably because of aberrant DTR expression on nonimmune cells, such as epithelial cells of the gut [7]. Therefore, experiments involving prolonged DC depletion require the use of radiation chimeras in which wild-type mice are reconstituted with CD11c.DTR bone marrow. As nonimmune cells in such chimeras remain of nontransgenic origin and, therefore, cannot express DTR, the deleterious effects of DT on mouse health are obviated.

Table 1. Overview of mouse models discussed in the text
Mouse modelCell types depletedRef.
Inducible depletion
CD11c.DTR/ CD11c.DOG/ CD11c.LuciDTRcDCs and pDCs, but also certain macrophages, plasmablasts, activated T cells, NK cells, and Ly-6Clow monocytes[6, 29, 30]
zDC.DTRcDCs and probably certain activated monocytes[12]
Langerin.DTRLCs, Langerin+ dermal DCs, and certain lymphoid tissue DCs[14, 15]
BDCA2.DTR/ SiglecH.DTRpDCs[19, 20]
Clec9a.DTRCD8α+ DCs and, likely, nonlymphoid tissue CD103+ CD11b DCs. Partial depletion of pDCs.[23]
CD205.DTRCD8α+ DCs, dermal DCs, and LCs[27]
Constitutive deficiency
CD11c.DTAcDCs, pDCs, LCs, and possibly certain macrophages, plasmablasts, activated T cells, NK cells, and Ly-6Clow monocytes[31, 32]
Langerin.DTALCs[18]
Batf3−/−CD8α+ DCs, nonlymphoid tissue CD103+ CD11b DCs[29]

The existence of radioresistant DCs such as LCs, as well as a subset of dermal DCs [8], can complicate the interpretation of DC depletion experiments carried out with CD11c.DTR chimeras. To overcome this problem, Hochweller et  al. [9] used a bacterial artificial chromosome approach to express a DTR transgene regulated by the CD11c locus control region (CD11c.DOG mice, Table 1), which allows for tighter restriction of DTR expression to CD11c+ cells. CD11c.DOG mice tolerate multiple DT injections, thus making them a better-suited model for long-term depletion studies. Although CD11c.DTR and CD11c.DOG mice have proven useful to study DC biology, it is important to mention that CD11c expression is not restricted to DCs. Indeed, CD11c is also found on some macrophages, plasmablasts, activated T cells, NK cells, and Ly-6Clow monocytes and many of these cell populations are depleted in both CD11c.DTR and CD11c.DOG mice upon DT injection [6, 9, 10]. In fact, CD11c.DTR mice have, in some instances, been used as a tool not to deplete DCs but macrophages [11].

To overcome this lack of DC-restricted expression, another cDC-depletion mouse model has recently been generated, in which a DTR transgene is inserted into the 3' untranslated region of the Zbtb46 (zDC) gene (zDC.DTR mice, Table 1) [12]. In the immune system, Zbtb46 gene expression appears to be restricted to cDCs and certain activated monocytes. Zbtb46 is not expressed by pDCs, macrophages or other immune cells [12, 13], making it a suitable candidate for cDC depletion. Consequently, in zDC.DTR mice injected with DT, only cDCs and, likely, some activated monocytes are depleted. However, a single injection of DT is lethal in these mice, probably due to Zbtb46 expression in committed erythroid progenitors and endothelial cells, in addition to its expression on cDCs [13]. As such, similar to the situation with CD11c.DTR mice, cDC ablation studies in zDC.DTR mice necessitate the use of radiation chimeras generated by reconstitution of wild-type mice with zDC.DTR bone marrow. Such chimeras consequently suffer from the limitation of the lack of depletion of the radioresistant DC subsets.

Several other DTR mouse models have been generated with the purpose of inducibly depleting specific DC subsets rather than all DCs (Table 1). Two groups independently generated mice in which a DTR-containing transgene was inserted into the Langerin locus, either via a knock-in approach or insertion into the 3′ untranslated region [14, 15]. While Langerin is predominantly expressed on LCs, it is also expressed on certain dermal DCs and other lymphoid tissue DC populations. Therefore, DT treatment of Langerin.DTR mice not only ablates LCs, but also a fraction of dermal DCs. This problem can be overcome by critically timing experiments after a single DT injection, as dermal DCs start to reappear as early as day 5, while LCs remain depleted for more than 2 weeks [15, 16]. Alternatively, one can take advantage of the radioresistance of LCs and make radiation chimeras in which Langerin.DTR mice are reconstituted with wild-type bone marrow [17]. An additional model of LC ablation relies on expression of the toxic A chain of DT (DTA) under the control of the human Langerin promoter (Langerin.DTA mice) [18]. This mouse displays constitutive ablation of LCs but, likely due to properties of the promoter used, retains Langerin+ dermal DCs (Table 1) [16, 18].

To inducibly deplete pDCs in mice, two models have recently been described. The first uses the promoter of human blood DC antigen 2 (BDCA-2), which is exclusively expressed on pDCs in humans, to drive expression of a DTR transgene (BDCA2.DTR mice, Table 1) [19]. Treatment of BDCA2.DTR mice with DT specifically depletes pDCs [19]. However, the BDCA-2 gene is not present in the mouse and it is therefore conceivable that the human BDCA-2 promoter could give rise to off-target DTR expression in some instances. In the second model, a DTR transgene was inserted into the 3′ untranslated region of the SiglecH gene (SiglecH.DTR mice, Table 1) [20]. SiglecH is highly expressed on pDCs, but is also found at lower levels in cDCs and certain macrophages [19, 21, 22]. Nevertheless, DT administration to SiglecH.DTR mice appears to selectively deplete pDCs without affecting other immune cells [20]. However, due to transgene interference with expression from the SiglecH locus, homozygous SiglecH.DTR mice are in fact deficient in SiglecH expression, complicating the interpretation of results obtained in these mice [20].

Recently, two additional mouse models have been described to deplete CD8α+ DCs. The Clec9a.DTR model uses a bacterial artificial chromosome to express DTR under the control of the Clec9a locus [23]. DNGR-1, the product of the Clec9a locus, is expressed on CD8α+ DCs in lymphoid tissues and these cells are depleted in Clec9a.DTR mice upon DT treatment [23]. Given that DNGR-1 is also expressed on the related CD103+ CD11b DCs in nonlymphoid tissues [24], these cells are expected to also be depleted in the same model, although this remains to be demonstrated. pDCs, which express low levels of DNGR-1 [25, 26], are also partially reduced by DT treatment in Clec9a.DTR mice, complicating the interpretation of results [23].

The second model to deplete CD8α+ DCs is based on the expression of DTR under control of the CD205 locus (CD205.DTR mice) and was generated by inserting a DTR transgene into the 3′ untranslated region of the CD205 gene. CD205 is predominantly expressed on CD8α+ DCs, dermal DCs, LCs and cortical thymic epithelium [27]. CD205.DTR mice die upon DT injection and, therefore, the authors used irradiated wild-type mice reconstituted with CD205.DTR bone marrow to demonstrate that DT injection depletes CD205+ DCs, but not radioresistant cortical thymic epithelial cells or LCs [27].

Langerin.DTR, BDCA2.DTR, SiglecH.DTR, Clec9a.DTR, and CD205.DTR mice all provide a means to deplete specific subsets of DCs. Although these models should prove useful in dissecting the functions of different DC subtypes, it is possible that, by depleting one subset, others might take over some of the functions of the depleted subset, which could result in an underestimation of the physiological role of the depleted subset. Recent data obtained with mice lacking the transcription factor BATF3 (Table 1) indicate that this need not always be the case. Batf3-deficient mice, particularly on a 129/Sv genetic background, exhibit a selective block in the development of CD8α+ DCs and CD103+ CD11b DCs [28, 29]. Notably, these mice display marked defects in the ability to mount cytotoxic T-cell responses to tumors and certain viruses, as well as in resisting parasites such as Toxoplasma gondii [28, 29]. Similarly, DT injection into Clec9a.DTR mice results in resistance to induction of cerebral malaria, probably because of a reduction in priming of Plasmodium-specific CD8+ T cells that induce pathology [29]. Finally, Langerin.DTR and DTA mice have revealed roles for LCs in immune responses and tolerance [14, 18]. Thus, the availability of mouse models for DC-subset depletion sheds light on the role of DC subtypes in immune regulation.

CD11c.DTR and CD11c.DOG models are widely used to study the overall role of DCs irrespective of subset. Importantly, both model systems display neutrophilia and monocytosis upon DT injection [18, 30]. This phenomenon had already been reported by Hochweller et  al. [9], but its functional implications have only recently begun to be appreciated. For example, a recent study by Tittel et  al. [30] observed increased bacterial clearance in DT-treated CD11c.DTR and CD11c.DOG mice as compared with noninjected controls in a bacterial pyelonephritis model. This unanticipated result was not because the presence of DCs restrained bacterial elimination. Rather, it appears to be a by-product of the rapid influx of neutrophils into the kidney upon DT injection. Both CD11c.DTR and CD11c.DOG mice exhibit two waves of neutrophilia: An “early” wave that is manifest 24 h after DT injection and a “late” wave beginning at 72 h after DT injection. The “early” neutrophilia is due to the release of neutrophils from the bone marrow in response to chemokines CXCL1 and CXCL2 [30]. In contrast, the “late” neutrophilia is a consequence of increased granulopoiesis, likely caused by increased levels of Flt3L (fms-related tyrosine kinase 3 ligand), similar to what has previously been observed in CD11c.DTA mice (Table 1), which constitutively lack DCs [31, 32].

A new CD11c-based DTR mouse model (CD11c.LuciDTR, Table 1) generated by Tittel et  al. [30] exhibits the ‘late’ but not the "early" neutrophilia upon DT treatment. Although the mechanism remains elusive, these data imply that the "early" neutrophilia does not result from a direct interplay between DC function and neutrophil recruitment, but, rather, relates to the actual mouse model used to deplete DCs. Importantly, because neutrophils are the main effector cells involved in bacterial clearance, neutrophilia can explain the resistance conferred by DT injection in the pyelonephritis model. Interestingly, the CD11c.LuciDTR mice exhibit increased bacterial burden after DT injection in the same pyelonephritis model. Thus, in the absence of the confounding effects of the early neutrophilia, a role for CD11c+ cells in reducing rather than increasing pathogen burden can be revealed.

The findings of Tittel et al. [30] raise the question of whether the conclusions from other studies using CD11c.DTR or CD11c.DOG mice need to be revised. For example, in a recent study, Autenrieth et  al. [33] found that animal survival was significantly increased upon DC depletion in CD11c.DOG mice in a model of Yersinia enterocolitica infection and that the enhanced survival was mediated by increased neutrophil and monocyte activity. The authors concluded that DCs could regulate neutrophil and monocyte function in the steady state as well as during bacterial infection. However, when considering the results of Tittel et  al. [30], it is also possible that enhanced survival was due to increased bacterial killing by recruited neutrophils. Thus, DCs could have a smaller role in the regulation of phagocyte activity than might be apparent at first glance [33].

Similarly, in a model of peripheral vesicular stomatitis virus (VSV) infection, DC depletion in CD11c.DTR mice did not affect viral clearance in the first 48 h, even though type I interferon production, which is critical for early VSV clearance, was markedly impaired [34]. These unexpected results could again be explained by the induction of neutrophilia and monocytosis in CD11c.DTR mice, as neutrophils and monocytes can mount an early innate immune response that limits viral replication. If this were the case, the authors’ conclusion that DCs are of limited importance to the early response to peripheral VSV infection would need to be revised [34]. Of note, some of the DC-depleted mice failed to control virus replication in the brain and developed fatal VSV encephalitis, suggesting that the brain might be excluded from any protective neutrophilia and monocytosis induced by DT treatment of CD11c.DTR mice [34]. Interestingly, the same study showed that after DC depletion VSV-specific CD4+ T-cell responses were not affected, while the expansion of CD8+ T cells was severely impaired [34]. As DCs have been ascribed a crucial role in both CD4+ and CD8+ T-cell activation, the unaltered CD4+ T-cell response is surprising. The authors suggest that there might be another antigen-presenting cell, such as a macrophage, that supports CD4+ T-cell priming. While this may certainly be the case, it is important to determine to what extent such antigen-presenting macrophages/DCs are a result of the monocytosis induced by DC depletion.

In summary, although the CD11c.DTR and CD11c.DOG mouse models are useful tools to study DC biology, the depletion of immune cells other than DCs and the induction of neutrophilia and monocytosis in these models upon DT administration must be taken into account when interpreting results. As both neutrophils and monocytes are versatile innate immune cells, DC functions may be either over- or underestimated in CD11c.DTR and CD11c.DOG mice, depending on the experimental setup. In this light, it is essential to determine whether other inducible DC-depletion models (e.g. zDC.DTR, Langerin.DTR, BDCA2.DTR, SiglecH.DTR, Clec9a.DTR, and CD205.DTR mice) also exhibit neutrophilia and monocytosis upon DT injection. Of note, zDC.DTR mice have been reported to possess increased neutrophil counts in the spleen upon DT treatment [12]. Our understanding of DC biology would greatly benefit from a mouse model that combines specific depletion of DCs without the induction of neutrophilia and monocytosis.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Acknowledgements
  4. Conflict of interest
  5. References

Work at the London Research Institute is funded by Cancer Research UK. C.R.S. acknowledges additional support in the form of a prize from Fondation Bettencourt-Schueller and a grant from the European Research Council. J. v B. is supported by the Boehringer Ingelheim Fonds. B.U.S. was supported by an EMBO long-term Fellowship.

Conflict of interest

  1. Top of page
  2. Abstract
  3. Acknowledgements
  4. Conflict of interest
  5. References

The authors declare no financial or commercial conflict of interest.

References

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  2. Abstract
  3. Acknowledgements
  4. Conflict of interest
  5. References
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Abbreviations
pDC

plasmacytoid DC

cDC

conventional DC

DT

diphtheria toxin

DTA

diphtheria toxin A

DTR

diphtheria toxin receptor

LC

Langerhans cell

VSV

vesicular stomatitis virus