B Cell Development: The Impact of the Environment

B lymphocytes develop from pluripotent stem cells, and differentiate to plasma cells (PCs) in reaction to signals from the supportive microenvironment. Different sets of signals, which are derived from multiple sources such as soluble cytokines and cell-cell contacts, are required at different stages of development. For instance, murine B cell progenitors require the action of interleukin-7 (IL-7) in the early phase of their development in the bone marrow (BM). The necessity for IL-7 decreases as the cell matures, and this event is correlated with the appearance of CD22. The first two chapters of this thesis focus on the early stages of B cell development that take place in the BM. In chapter 1, I examine the IL-7 response and, although I do not show a specific role for CD22 in the loss of sensitivity to IL-7, my data suggest that cis interactions involving sialic acids might modulate the IL-7 response. This section is followed by the analysis of the effect of IL-21 on B cell progenitors in the BM. IL-21 is known to regulate the terminal stages of B cell differentiation. In collaboration with Dr. Danijela Konforte, I present evidence that B cell progenitors in the BM also express a functional IL-21 receptor and that stimulation of this receptor with IL-21 accelerates the maturation pace of B cells. I further demonstrate that proB cells stimulated with IL-21 and anti-CD40 can differentiate into immunoglobulin (Ig)-secreting cells, and discuss the possibility that IL-21 plays a role during inflammation for the development of B cell progenitors in peripheral lymphatic organs. Finally, in the last chapter, in collaboration with the laboratory of Dr. Gommerman, I investigate how the microenvironment can shape the development of B cells. It has been demonstrated by my collaborators that IgA+ PCs present in the gut produce iNOS and display traits commonly associated to the myeloid lineage, and in this chapter, I describe a co-culture system with BM and gut stroma to study the conditions that sustain the generation of IgA+iNOS+ cells. In particular, I show that the presence of microbial products is one of the key factors required for their development.Ph