Abstract
X-linked immune-deficient (Xid) mice, carrying a mutation in Bruton’s tyrosine kinase (Btk), have multiple B cell lineage differentiation defects. We now show that, while Xid mice showed only mild reduction in the frequency of the late transitional (T2) stage of peripheral B cells, the defect became severe when the Xid genotype was combined with either a CD40-null, a TCRbeta-null or an MHC class II (MHCII)-null genotype. Purified Xid T1 and T2 B cells survived poorly in vitro compared to wild-type (WT) cells. BAFF rescued WT but not Xid T1 and T2 B cells from death in culture, while CD40 ligation equivalently rescued both. Xid transitional B cells ex vivo showed low levels of the p100 protein substrate for non-canonical NF-kappaB signalling. In vitro, CD40 ligation induced equivalent activation of the canonical but not of the non-canonical NF-kappaB pathway in Xid and WT T1 and T2 B cells. CD40 ligation efficiently rescued p100-null T1 B cells from neglect-induced death in vitro. These data indicate that CD40-mediated signals, likely from CD4 T cells, can mediate peripheral transitional B cell maturation independent of Btk and the non-canonical NF-kappaB pathway, and thus contribute to the understanding of the complexities of peripheral B cell maturation.
Highlights
Report has shown that depletion of CD4 T cells in Xid mice led to a maturation block downstream of transitional B cells[35]
While an early report indicated that B cell receptor (BCR)-mediated signals might be useful primarily from the T2 stage onwards[36], it is recognized that signals from the BCR and BAFF-R are integrated for this transition[10]
Our data indicate that the T1 to T2 transition in Xid B cells is dependent on the availability of CD40-mediated signals probably from CD4 T cells, and that these CD40-mediated signals are independent of the non-canonical NF-kappaB pathway, unlike the pathway mediated by cross-talk between the BCR and the BAFF-R
Summary
Report has shown that depletion of CD4 T cells in Xid mice led to a maturation block downstream of transitional B cells[35]. The signal integration indicated by the Xid+nu/nu or the Xid+CD40-null double-mutant genotypes has not been examined for its role in this critical transition On this background, we have examined the stages of peripheral B cell maturation in Xid mice in comparison to Xid mice lacking alpha-beta T cells, CD40 or MHCII, as well as the survival and maturation in vitro of T1 and T2 B cells from Xid and WT mice. Our data indicate that the T1 to T2 transition in Xid (but not in WT) B cells is dependent on the availability of CD40-mediated signals probably from CD4 T cells, and that these CD40-mediated signals are independent of the non-canonical NF-kappaB pathway, unlike the pathway mediated by cross-talk between the BCR and the BAFF-R These data provide evidence for redundancies in the pathways mediating peripheral B cell maturation and survival
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