B-1a Cell Development in Splenectomized Neonatal Mice.

Gabriel K Pedersen,Bruce Beutler,Xiaohong Li,Sharesta Khoenkhoen,Monika Ádori,Gunilla B Karlsson Hedestam

doi:10.3389/fimmu.2018.01738

Abstract

B-1a cells are mainly generated from fetal liver progenitor cells, peri- and neonatally. The developmental steps and anatomical sites required for these cells to become mature B-1a cells remain elusive. We recently described a phenotypically distinct transitional B cell subset in the spleen of neonatal mice that generated B-1a cells when adoptively transferred. This, in combination with findings demonstrating that B-1a cells are lacking in congenitally asplenic mice, led us to hypothesize that the neonatal spleen is required for B-1a cell development. In accordance with previous reports, we found that B-1a cell numbers were reduced in adult mice that had undergone splenectomy compared to after sham surgery. In contrast, neonatal splenectomy led to peritoneal B-1a cell frequencies comparable to those observed in sham-operated mice until 6 weeks after surgery, suggesting that an intact spleen is required for B-1a cell maintenance rather than development. To study the role of the prenatal spleen in generating B-1a cells, we transferred fetal liver cells from pre-splenic embryos [embryonic age 11 (E11) days] into splenectomized recipient mice. B-1a cells were generated in the absence of the spleen, albeit at slightly reduced frequencies, and populated the peritoneal cavity and bone marrow. Lower bone marrow B-1a cell frequencies were also observed both after neonatal and adult splenectomy. These results demonstrated that B-1a cells could be generated in the complete absence of an intact spleen, but that asplenia led to a decline in these cells, suggesting a role of the spleen for maintaining the B-1a compartment.

Highlights

Congenital asplenia, or splenectomy, leads to increased susceptibility to infections with encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae [1, 2], but the causes for this are poorly understood
To investigate if neonatal splenectomy had an impact on B cell progenitors, we examined these in the bone marrow 6 weeks after neonatal splenectomy (Figure 3E; Figure S2A in Supplementary Material)
The risk of sepsis is 10–20 times higher in splenectomized individuals than in the general population and children born with isolated asplenia often die during the first months of life from sepsis ascribed to bacterial infections at mucosal sites [25,26,27]

Summary

Introduction

Congenital asplenia, or splenectomy, leads to increased susceptibility to infections with encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae [1, 2], but the causes for this are poorly understood. B-1a cells protect against encapsulated bacteria by constitutively secreting broadly reactive natural IgM antibodies [7, 8] and it was reported that removal of the spleen in adult mice leads to reduced B-1a cell frequencies, demonstrating that the spleen is either required for maintenance and/or for development of B-1a cells [3, 9,10,11]. Further indications that the spleen is required for B-1a cell development came from analysis of mice with congenital asplenia due to absence of the Tlx (Hox11) gene since, in these mice, B-1a cells were essentially absent. The underlying mechanisms for the lack of B-1a cells under asplenic conditions, remain unknown [3].

Methods

Results

Conclusion