Does CD40 Ligation Induce B Cell Negative Selection?

Abstract

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 (κEP-CD154). Precursors beyond pro-B cells were absent in adult bone marrow but were increased in the fetal liver. Newborn κEP-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, κEP-CD154 mice were hypogammaglobulinemic, indicating that the expanded population of apparently activated B cells was nonfunctional. Further analysis revealed that soon after birth, κEP-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.

CD154-CD40 interactions in the control of murine B cell hematopoiesis

“…We show here that in contrast to the findings in many previous studies but in agreement with the study of Martínez-Barnetche et al [19], CD40 is expressed on murine B cells from the earliest progenitors (pro-B cells) onward. More exactly, CD40 is expressed on the Fr B pro-B cells, which is the first population to express rag 1 and rag 2 gene transcripts and is the first population to have undergone some heavy chain rearrangement.…”

“…Our data overall agree with and in part contradict the findings of the Moreno group [19]. This group showed, like us, that CD40 expression on murine pre-B cells was not restricted to pre-B cells onward but that some expression could be found on pro-B cells.…”

“…For instance, it has been shown that sustained, as opposed to transient stimulation through CD154, can inhibit B cell terminal differentiation [21, 32], and we have shown that stable transfection of allogeneic donor cells with CD154 can have inhibitory effects on alloantibody responses against the transfected cells following transplantation [33], and in most instances, CD154 expression has been shown to have stimulatory effects on immune responses [5, 10, 26]. Whether the loss of Fr C in the BM of the transgenic mice produced by the Moreno group [19] represented an arrest of differentiation or an exit of precursor cells to other sites was not addressed specifically by this group, although notably, the authors did observe hematopoietic foci in the spleens of their mice, suggesting perhaps that the loss of Fr C in BM was at least partially a result of migration. The Moreno group concluded [19] that CD40 ligation, during B cell ontogeny, had a negative regulatory effect on hematopoiesis in the marrow.…”

Potential role of CARMA1 in CD40‐induced splenic B cell proliferation and marginal zone B cell maturation

“…CD40 belongs to the super-family of TNF receptors, and expression of CD40 is detected during early B cell ontogeny [27][28][29][30]. In mature B cells, signaling through CD40 promotes survival, somatic hyper-mutation and class-switch recombination, and the defective CD40 signaling results in hyper-IgM syndrome [31,32].…”

Is Autoimmunity a Component of Natural Immunity to HIV?

“…CD40 and Fas pathways interact in triggering apoptosis, both in pre-B cell and in B cells that have successfully completed B cell receptor rearrangement [3,103,82]. Cytokines and soluble factors also control B cell survival.…”