The architecture of the spleen — with specialized regions containing subsets of B cells, T cells and antigen-presenting cells (APCs) — is designed to ensure a rapid and efficient response to blood-borne pathogen antigens. A new study in The Journal of Experimental Medicine shows that a specialized subset of macrophages might be the architects responsible for careful planning of the marginal zone of splenic white pulp.

The marginal zone contains a population of B cells (MZBs) and specialized marginal-zone macrophages (MZMs), which are defined in part by expression of the scavenger receptor Marco. Mice that lack the inositol polyphosphate phosphatase Ship have splenomegaly and disruption of this marginal-zone architecture, with the loss of MZBs and the redistribution of Marco+ MZMs to the red pulp. As Ship is expressed by almost all haematopoietic cells, the authors conditionally disrupted Ship in macrophages and showed that the disrupted marginal-zone phenotype can be attributed to a primary macrophage defect. This was confirmed by the injection of Ship-deficient and wild-type bone marrow into irradiated wild-type recipients; both types of bone marrow contributed equally to the MZB population, which shows that Ship-deficient B cells can still give rise to MZBs.

Ship is known to be a negative regulator of cell signalling. In B cells, it achieves this by inhibiting the association of the Tec-family kinase Btk with the cell membrane, which raises the threshold for stimulation. As Btk is also expressed by macrophages, is the increased activity of Btk as a result of Ship deficiency in MZMs responsible for the disrupted architecture? Mice that were deficient for both Ship and Btk had a normal marginal-zone structure, which indicates that although other Tec-family kinases are also expressed by macrophages, the specific inhibition of Btk by Ship is essential for the white-pulp organization.

MZMs, but not other types of macrophage and APC, were preferentially depleted from the spleen. This resulted in a reduction in the number of MZBs in the marginal zone. Marco has a domain that has been proposed to bind to activated B cells, so the authors looked at whether Marco can bind to MZBs. The extracellular domains of Marco were used to stain splenic populations and maximal staining occurred for MZBs. Furthermore, injection of a Marco-specific antibody in wild-type mice disrupted the marginal zone. Therefore, the Marco–MZB interaction is a mechanism for the retention of MZBs in the marginal zone by MZMs.

So, just as there would be no Eiffel Tower without Gustave Eiffel, this study shows that without Marco+ MZMs, there is no splenic marginal zone containing specialized B cells ready to respond to pathogen antigens.