Immune cell transdifferentiation: a complex crosstalk between circulating immune cells and the haematopoietic niche.

Conventional wisdom states that reactive oxygen species (ROS) are deleterious to living organisms. Indeed, neutrophils and macrophages use a respiratory burst to kill ingested microbes. Nevertheless, ROS at low doses can convey important biological information to regulate plant cell growth, for example, or as a prerequisite for the differentiation of some haematopoietic progenitor cells in insects (Owusu-Ansah & Banerjee, 2009). These effects had been thought to be largely cellautonomous. However, in this issue of EMBO reports, the Banerjee group shows that parasitization of Drosophila larvae by wasp eggs leads to increased ROS levels in haematopoietic niche cells, which then emit a diffusible signal required for the trans differentiation of haemocytes into a cell type adapted to kill parasites (Sinenko et al, 2011). Drosophila has become an interesting model to study haematopoiesis, as many signalling pathways and transcription factors that regulate this process are conserved between humans and Drosophila. The Notch, Hedgehog, JAK–STAT and Wingless pathways, as well as Collier/EBF, have been shown to control blood cell homeostasis in the lymph glands (Crozatier & Vincent, 2011). However, in contrast to the plethora of cytokines that are known to participate in the control of mammalian haematopoiesis, almost no such molecules have been identified in Drosophila, with the notable exception of a ligand for the receptor of the sole JAK–STAT pathway that exists in flies. Drosophila—which lacks a lymphoid lineage and, hence, an adaptive immune system—provides a simple, genetically tractable system for the study of haematopoiesis. It starts during embryogenesis, generating a population of circulating and sessile haemocytes in larvae, which are mostly plasmatocytes—macrophage-like cells—and crystal cells (Lanot et al, 2001). We refer to them as haemocoelic haemocytes. A haematopoietic organ, the lymph gland, develops during larval stages, and at the onset of pupation releases the haemocytes required to control infections during metamorphosis and involved in tissue remodelling. In vertebrates, haematopoietic stem cells can either self-renew or differentiate, decisions that are controlled by signals provided by the haematopoietic ‘niche’. The niche consists of a structural microenvironment that sustains the longterm renewal of stem cells. A similar structure, called the posterior signalling centre (PSC), exists in the Drosophila lymph gland and, under normal conditions, maintains a pool of neighbouring precursor cells (prohaemocytes) in an undifferentiated state in the medullary zone (Crozatier & Vincent, 2011). This is achieved in a non-cellautonomous manner, by delivering cues— including a Hedgehog signal—and thus keeping prohaemocytes in a quiescent precursor state, a process that also requires autocrine JAK–STAT signalling in the medullary zone prohaemocytes. Enhanced ROS expression in progenitor cells of the medullary zone is required for their subsequent differentiation into haemocytes (Owusu-Ansah & Banerjee, 2009). A major threat to any insect larva in its natural environment is parasitoid attacks by wasps. These hymenopterans also lay their eggs in Drosophila larvae, where they develop at the expense of the host. Once the Drosophila larva pupates, the parasitoid larva undergoes metamorphosis, consumes the host, and a wasp adult emerges from the fly pupal case. To fight such infestation, Drosophila larvae have developed a spectacular cellular response: on detection of the parasitoid egg, their immune system triggers the massive differentiation of prohaemocytes in the lymph gland and the transdifferentiation of circulating and/or sessile plasmatocytes into a specialized blood cell type—the lamellocyte (Fig 1; Lanot et al, 2001; Markus et al, 2009). The abundant newly formed lamellocytes then eliminate the invader by encapsulating the wasp egg, which is eventually killed within the melanized capsule. Although wasps have evolved strategies to escape this vigorous defence mechanism, the fly can thereby limit parasitoid developmental success.