Localization and Differential Expression of Activation-Induced Cytidine Deaminase in the Amphibian Xenopus upon Antigen Stimulation and during Early Development

Abstract

As in mammals, B cell maturation in the amphibian Xenopus involves somatic hypermutation (SHM) and class switch recombination to diversify the B cell receptor repertoire in response to Ag stimulation. Unlike mammals, however, the resulting increase in Ab affinity is poor in Xenopus, which is possibly related to the absence of germinal centers and a suboptimal selection mechanism of SHM. In mammals, both SHM and class switch recombination are mediated by the activation-induced cytidine deaminase enzyme and under Ag-dependent regulation. Given its evolutionary conservation in jawed vertebrates, we used activation-induced cytidine deaminase as a marker to monitor and localize B cell maturation in Xenopus upon immune responses and during early development. In adult, Xenopus laevis AID (XlAID) was detected mainly in the spleen, where cells expressing XlAID were preferentially distributed in follicular B cell zones, although some XlAID+ cells were also found in the red pulp. XlAID was markedly up-regulated in the spleen with different kinetics upon bacterial stimulation and viral infection. However, during secondary anti-viral response XlAID was also noticeably expressed by PBLs, suggesting that XlAID remains active in a subset of circulating B cells. During ontogeny, XlAID expression was detected as early as 5 days postfertilization in liver before the first fully differentiated B cells appear. Concomitant with appearance of mature B cells XlAID was up-regulated upon bacterial stimulation or viral infection at later larval stages. This study highlights the conserved involvement of XlAID during Ag-dependent B cell responses in Xenopus but also suggests another role in B cell differentiation earlier in ontogeny.

Innate Immune Responses and Permissiveness to Ranavirus Infection of Peritoneal Leukocytes in the FrogXenopus laevis

“…The increase in IgM ϩ B cells at 6 dpi is interesting since we have reported that some B cells proliferate in the spleen during FV3 infection (24,31) and that activated B cells expressing activation-induced cytidine deaminase are present in the periphery (26). The drop in T-cell numbers at 3 dpi, on the other hand, is intriguing.…”

Cytidine deaminases: AIDing DNA demethylation?

“…Further suggestions of functions for AID beyond the immune system come from studies of lower vertebrates. As in mice, AID is expressed during early development in Danio rerio (Rai et al 2008), Xenopus laevis (Marr et al 2007), and the newt Pleurodeles waltl (Bascove and Frippiat 2010). The broad conservation of this pattern of AID expression strongly suggests a function in early development.…”

Early B blasts acquire a capacity for Ig class switch recombination that is lost as they become plasmablasts

“…We show here that AID induced by NP-Ficoll is expressed at lower levels than in GC blasts and is not coexpressed with Bcl6. Germinal center independent class switching may represent an ancient pathway of AID induction that developed before proper germinal centers evolved, as is seen in lower vertebrates that develop plasma cells and undergo CSR in the absence of germinal centers [24]. CSR occurring before affinity maturation happens may seem counterproductive, as a switch from IgM to IgG leads to a loss of avidity of the resulting antibody.…”