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Reply to: "Can DCs be distinguished from macrophages by molecular signatures?"

Nature Immunology volume 14, pages 189–190 (2013)Cite this article

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Randolph and Merad respond:

Two articles from our groups and the ImmGen Consortium have reported the transcriptional analysis of DCs1 and macrophages2. Hume et al. raise several objections to those reports, including the main underlying concern that non–lymphoid tissue DCs are in fact erroneously classified as DCs, rather than macrophages. They argue that the term 'DC' should be strictly reserved for the original definition of this cell as a lymphoid organ–resident cell population that is nonphagocytic and dependent on the receptor tyrosine kinase Flt3. First, that definition disregards recognition by the entire DC field, including the author of the original definition, that all DCs have a phagocytic phase of their life cycle that was missed in the earliest studies in this field, probably because of DC maturation induced by lipopolysaccharide contamination of the albumin used to float these low-density cells. Second, there is ample evidence beyond our transcriptional analyses that non–lymphoid tissue DCs are counterparts to the lymphoid DCs originally defined. For example, mouse CD8a+ DCs have considerable similarity to non–lymphoid organ CD103+ DCs, with both being derived from DC-restricted precursors and having a unique dependence on the Flt3 ligand3 and the transcription factors Batf3 (refs. 4,5), Id2 and IRF8 (refs. 3,5) for their development and homeostasis. In addition, CD8+ DCs and CD103+ DCs excel in the cross-presentation of antigens4,6,7,8,9 and have a considerable propensity to engulf apoptotic cells10,11 as a source of antigens for cross-priming. Nonlymphoid tissues are also populated by DCs that are phenotypically distinct from CD103+ DC, called 'CD11b+ DCs'. Non–lymphoid tissue CD11b+ DCs usually lack the expression of CD103 (except in the gut), express the integrin CD11b and are heterogenous for the macrophage-associated marker CSF1R and for the DC-associated marker Flt3. 'Nonlymphoid–tissue CD11b+ DCs' remain the main source of confusion in distinguishing macrophages from DCs because they are mixed populations formed by macrophages and true DCs12, as has been shown for gut CD11b+ DCs13. Two independent studies have established that the zinc-finger transcription factor Zbtb46 is expressed only by DCs, including non–lymphoid organ CD11b+ DCs14,15, but not by macrophages or any other hematopoietic cells, except erythroid cells. Correspondingly, our article has independently identified Zbtb46 as being associated with DC identity1. The use of the macrophage markers Mertk and CD64 as well as the DC-restricted transcription factor Zbtb46 should help analyses revisiting the contribution of macrophages and true DCs to the population of CD11b+ DCs in non–lymphoid organs. Thus, the core of the objection by Hume et al. is far more extensive than an objection to our methodology in DC transcriptional profiling but is instead an objection to the concept of DCs in general.

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Authors and Affiliations

  1. Department of Pathology & Immunology, Washington University, St. Louis, Missouri, USA

    Gwen Randolph

  2. Immunology Institute and The Tisch Cancer Institute Mount Sinai School of Medicine, New York, New York, USA

    Miriam Merad

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  1. Gwen Randolph
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Randolph, G., Merad, M. Reply to: "Can DCs be distinguished from macrophages by molecular signatures?". Nat Immunol 14, 189–190 (2013). https://doi.org/10.1038/ni.2517

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