Simply mention the term "dendritic cell subtypes" or "dendritic cell development" to some immunologists, or even dendritic cell (DC) biologists, and their eyes will glaze over. While it’s well accepted that this unique family of white blood cells kick-start the immune response, it can be quite difficult to sort the trash from the treasure in this controversial area.

I believe the high citation rate of this paper reflect my and Ken Shortman’s attempt to collate three decades of research in this area and present the DC lifecycle in a more digestible and logical format. We also highlight several new concepts that entice a rethink on the subject for those more involved in the area.

“This paper establishes a preliminary framework to consider the development of DC subtypes in more detail but with better context..”

This paper establishes a preliminary framework to consider the development of DC subtypes in more detail but with better context. We used evidence of i) organ location, ii) derivation from progenitors, iii) factor-dependency iv) presence in the steady-state versus inflammation, and v) representation in culture models, to make some broad definitions of the DC types and their development. Undoubtedly, there will be additional brushstrokes to this sketch in the future.

I often describe DCs as the "spies" or James Bond of the immune system. When they’re not in action, they’re "pacifying" some of the potentially dangerous female soldiers (T-cell tolerance to prevent autoimmune disease in the steady-state). But when activated, they take photographic snapshots (antigen presentation) of the invading enemy (infectious organism), jump into their Aston Martin (the lymphatics and bloodstream) back to the headquarters of the immune system (lymph nodes and spleen) and present their enemy dossier to the soldiers (T cells and B cells).

In this paper, we describe the different types of spies of the immune system, where they lie in wait for the enemy, and where they got their training. Some come from the "Roger Moore" school of training (steady-state resident pDCs, CD8+ and CD8– DCs), some from the "Sean Connery" school (migratory DCs) and others from the "Daniel Craig" school (inflammatory DCs). There may even be a "Pierce Brosnan" school not yet discovered—although that may be one we’d rather forget!

Through working in David Hume’s lab at the Institute for Molecular Bioscience at the University of Queensland, I became interested in antigen-presenting cells and the differences between macrophages and DCs. David is oft quoted saying "DCs are just macrophages, but without teeth." Along those lines, each DC subtype was regarded by many as simply a color in the myeloid rainbow but not a distinct lineage in their own right.

Previous work from Ken Shortman’s lab suggested otherwise, with evidence that the subtypes were "wired" differently and were distinct cell types. After I joined Ken’s lab at The Walter & Eliza Hall Institute (WEHI), our work dissected that different subtypes have distinct precursors, and not all are myeloid in origin.

As for problems, there were many. If you consider DCs are already one of the most rare cell types, imagine how infrequent their progenitors must be. In fact, I found out after the first one and a half years of my Ph.D. that my strategy to deplete irrelevant cells was removing DC precursors non-specifically. When I realized this, I threw my lab book in the bin and went to the pub with a close friend! On the following day at 1pm, red-eyed and unshaven, I started all over again with a different strategy.

The DC subtypes and their development are still an enigma. It is clear that they can be derived from both myeloid and lymphoid routes, but they are the only cell type able to do this—why? Do DCs arrive in a continuous flux from the bone marrow, or develop within the organs themselves from long-term precursors?

What are the intrinsic and extrinsic factors involved in their development? Where do they fit into the haematopoietic map? Which subtype is important for which infection? Why do we need so many subtypes? What are the human equivalents of the mouse CD8+ and CD8– subtypes? More importantly, once the rules are established, which DC subtype will lead to a better application of this cell type in medicine?

Considering the power of DCs in initiating an immune response, many are attempting to train a patient’s DCs to fight cancer and infection. While this strategy has had mixed success, it certainly holds promise. In fact, Ralph Steinman, head of the Laboratory for Cellular Physiology and Immunology at Rockefeller University, who discovered DCs, was awarded this year’s Albert Lasker Award for Medical Research. This award is often considered the prelude to the Nobel Prize…so watch this space!