Does CD40 ligation induce B cell negative selection

Binding of CD154 to its receptor, CD40, provides costimulation for mature B cell activation and differentiation in response to Ag receptor signals. In mice, early B cell precursors express CD40, but its function at this stage is unknown. We examined the effects of CD40 ligation during B cell ontogeny in transgenic mice constitutively expressing CD154 on B cells (EP-CD154). Precursors beyond pro-B cells were absent in adult bone marrow but were increased in the fetal liver. Newborn EP-CD154 mice had largely increased numbers of peripheral B cells, which were CD154, and that 36 h after birth expressed high surface levels of CD23 and MHC class II, resembling activated mature B cells. Nevertheless, EP-CD154 mice were hypogammaglobulinemic, indicating that the expanded population of apparently activated B cells was nonfunctional. Further analysis revealed that soon after birth, EP-CD154 mice-derived B cells became CD5/Fas, after which progressively decreased in the periphery in a CD154-CD40-dependent manner. These results indicate that CD40 ligation during B cell ontogeny induces negative selection characterized by either hyporesponsiveness or an arrest in maturation depending on the time of analysis and the anatomic site studied. The Journal of Immunology, 2002, 168: 1042–1049. T cell-dependent B cell activation begins with B cell Ag re-ceptor (BCR)3 cross-linking, followed by costimulatory mol-ecule and cytokine signals (1–3). The best characterized co-stimulatory signal for B cells is delivered by activated T cells by means of the TNF family molecule CD154 to CD40, a TNFR family member (4–7). The biological effects induced by CD40 ligation on