Perivascular clusters of dendritic cells provide critical survival signals to B cells in bone marrow niches Anita Sapoznikov et al. Nature immunology 2008; March 2

Background The bone marrow is generally considered a primary lymphoid organ that provides a unique microenvironment with defined niches for stem cells, lymphogenesis and myelogenesis. Early B cell development is confined to the bone marrow, immature B cells then leave the bone marrow and mature in the spleen. Notably, up to a quarter of the mature B cell pool positive for IgD and IgM can be found recirculating in the steady state through the bone marrow. Moreover, bone marrow–resident mature B cells can participate in situ in T cell–independent humoral immune responses to blood-borne microbes.

Background Bone marrow constitutes a storage site for terminally differentiated B cells. Mature CD4+ and CD8+ T cells continuously home to the bone marrow. Bone marrow represents a principal reservoir for both CD4+ and CD8+ memory T cells. Bone marrow–resident naive and memory T cells can both be activated in situ, which suggests the presence of ‘professional’ antigen- presenting cells in the bone marrow.

Question What is the phenotypic characterization and function of bone marrow–resident DCs (bmDCs)?

Characterization of bmDCs

Organization of bmDCs into perivascular clusters

Two-photon microscopy of cranial bone marrow cavities of x3cr1gfp/+ mice (bmDCs, green; blood vessels, red)

Two-photon microscopy of the colocalization of adoptively transferred B,T cells, host bmDCs and blood vessels in the bone marrow cavity of a Cx3cr1gfp/+ mouse

Conditional ablation of bmDCs

Ablation of bmDCs causes loss of recirculating B cells

The bmDCs provide a survival signal to mature B cells

The survival of mature B cells in bone marrow is independent of BAFF-producing bmDCs

B cells require MIF-producing bmDCs for survival Flow cytometry of mature B cells in the bone marrow for surface expression of CD44 and CD74, components of the MIF receptor complex

B220+CD93–CD23+ mature cells from the spleens and bone marrow of Mif –/– mice and wild- type control mice

splenic DCs in control wild-type mice reconstituted with bone marrow from Mif –/– mice and CD11c-DTRtg mice (Mif –/–;DTRtg-WT)

bone marrow and spleen B cell compartments of the following bone marrow chimeras: wild-type mice reconstituted with bone marrow from CD11c-DTRtg mice (DTRtg-WT), from Mif –/– mice and CD11c-DTRtg mice (Mif –/–DTRtg-WT) or from Baff –/– mice and CD11c- DTRtg mice (Baff –/–DTRtg-WT)

distribution of Mif –/– B cells (CD45.1–) and Mif +/+ B cells (CD45.1+) in the bone marrow B cell compartment.