Positive and Negative Selection During B Lymphocyte Development

Abstract

Our laboratory is interested in a variety of issues related to lymphocyte development. More specifically, we have focused on the processes that regulate the decision to commit to the B lymphocyte (B cell) lineage, then the subsequent signals that are involved in maintaining this commitment to the B cell lineage. These signals result in the positive selection of those B cells that properly execute the complex genetic changes associated with B cell development, then trigger the elimination of B cells that are responsive to self-antigens and, therefore, possess the potential to mediate autoimmune disease. Our general experimental approach has been to address these issues from the perspective of signal transduction. Our goal is to define the biochemical and genetic processes that are integrated in order to accomplish these selection processes. To do so, we employ in vivo animal models as well as more defined in vitro studies, using both primary and transformed cell lines. For the past several years, we have been primarily interested in the precise mechanisms by which the B cell antigen receptor (BCR), and intermediate forms of this receptor, regulate these complex developmental processes. We have used the ongoing studies described below as two representative examples of how we are approaching these issues and some of the insights that we have made. To place both of these studies in context, we will begin with a brief introduction into B cell development.

Human immune system mice: current potential and limitations for translational research on human antibody responses

“…Second, as discussed above, the majority of B cells in HIS mice appears to be rather immature and thus may respond to engagement of their BCRs in the absence of costimulation by undergoing apoptosis or becoming anergic [47][48][49]. Finally, the rather disorganized nature of the white pulp regions of the spleen and the limited number of LNs found in HIS mice would pose a barrier to B cell-accessory cell interactions that normally take place in defined regions of SLOs, as well as formation of germinal centers.…”

Differential signalling during B-cell maturation

“…Moreover, whilst certain distal signalling elements such as cPLA 2 (immature and GC B cells) display very restricted profiles of expression during B-cell maturation allowing ubiquitous signals such as Erk to dictate quite distinct functional outcomes in immature and mature B cells, many of the signalling differences identified between distinct maturation stages of B-cell development are rather more subtle. For example, whilst expression of some PTKs (Syk, Fyn and Fgr) NF-B, MAPKs, anti-apoptotic molecules such as Bcl-2, A1 and inhibitory co-receptors such as CD22 and Fc␥RIIB appears to be increased in the transition from immature to mature B cells, expression of Lyn, Btk, PLC␥2 and BLNK tends to be decreased [10,[131][132][133][134][135][136].…”

Vav proteins regulate peripheral B-cell survival

“…Figure 4B shows that CXCR5 was expressed at low levels on T1 cells but was increased on T2 and FO cells, which reside within B-cell follicles. 39,40 The levels of CXCR5 were similar on wild-type and Vav-deficient B cells. Taken together, these data indicate that Vav deficiency Wild-type or Vav-deficient mice were continuously administered BrdU and analyzed using antibodies for CD93, IgM, CD23, and BrdU at the indicated time points.…”