Seminars in Immunology 17 (2005) 175–182 Models for peripheral B cell development and homeostasis Bhaskar Srivastava a , R. Coleman Lindsley b , Neda Nikbakht a , David Allman a,∗ a Department of Pathology and Laboratory Medicine; University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6082, USA b Department of Pathology; Washington University School of Medicine, St. Louis, MO, USA Abstract Immature B cells undergo key maturation and selection events after migrating to peripheral lymphoid organs. We will review recent advances in our understanding of the cell populations and molecular interactions underlying the differentiation of immature peripheral B cells into mature marginal zone (MZ) and follicular B cells, and discuss potential mechanisms by which numbers of MZ and follicular B cells are maintained. We will also discuss current controversies over the identity of precursor cells for MZ and follicular B cells, and propose a potentially unifying model for precursor-product relationships in peripheral B cell maturation. © 2005 Elsevier Ltd. All rights reserved. Keywords: Transitional B cell; Marginal zone; Selection; Homeostasis; Development 1. Introduction In mammals B cells are generated from B-lineage com- mitted precursors in the fetal liver (FL) and bone marrow (BM). Newly formed B cells in the FL and BM are subjected to multiple selection pressures that function to both purge the nascent B cell pool of autoreactive and therefore potentially pathogenic B cells, and guide the differentiation of newly formed B cells into functionally distinct peripheral B cell compartments. In adults, newly formed B cells in the BM ultimately give rise to either follicular or marginal zone (MZ) B cells. Follic- ular B cells comprise the bulk of the peripheral B cell pool, are the main cellular constituent of the splenic and lymph node follicles, recirculate throughout the blood and lymphatic sys- tems, and contribute to the primary and memory humoral re- sponse by generating both primary antibody forming plasma cells and germinal center B cells. In contrast, MZ B cells con- stitute only some 5% of all peripheral B cells, are localized to the marginal sinus of the spleen, do not readily recircu- late, and contribute to the early primary humoral response. Significantly, MZ B cells appear to constitute a first-line of defense against blood-borne pathogens without contributing significantly to the memory B cell response, and thus may ∗ Corresponding author. Tel.: +1 215 746 5547; fax: +1 215 573 2350. E-mail address: dallman@mail.med.upenn.edu (D. Allman). be viewed as a cellular link between the innate and adaptive immune systems. Over the last decade it has become apparent that B cells are exported from the adult BM as functionally immature de- velopmental intermediates [1–4]. Thus, adult splenic B cells include three or more subsets of immature (or transitional) B cells that share many characteristics with newly formed B cells in the BM [2,4–6]. These findings raise the possibility that selection events that shape the overall composition of the peripheral B cell pool occur in the periphery as well as the BM. One long-standing question in peripheral B cell develop- ment is how transitional B cells are selected into the follicular versus MZ B cell compartments, and what signals function to maintain adequate numbers of cells in each population. In this review, we will discuss recent advances including several unpublished observations from our laboratory on the nature of transitional B cell subpopulations and the selective pres- sures that guide their selection into the long-lived follicular and MZ B cell pools. 2. Bcellpositiveselection Studies assessing the production and turnover rates of im- mature B cells in the marrow versus transitional and mature B cells in the periphery suggest that B cells must successfully transit multiple selection points in both the BM and periphery. 1044-5323/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.smim.2005.02.008