Switching ON Fetal B Lymphopoiesis

Research output: ThesisDoctoral Thesis (compilation)

Abstract

B-1a cells are innate-like lymphocytes that develop primarily during fetal and neonatal life, whereas adult bone marrow (BM) hematopoietic stem cells (HSCs) preferentially give rise to follicular B-2 cells. Functioning at the interface of the innate and adaptive immune systems, B-1a cells provide a non-redundant first line of defense prior to the temporally delayed establishment of a B-2 cell response. The underlying causes for the developmental attenuation in B-1a potential remain poorly resolved. HSCs undergo a functional switch in neonatal mice hallmarked by a decrease in self-renewing divisions and entry into quiescence. The timing of this switch around 3 weeks of age correlates with the change in B cell output from B-1a potent to predominantly B-2 restricted.
We hypothesized that the cellular basis for this developmental attenuation in B-1a cell output is a consequence of a shift in stem cell state during ontogeny. Using cellular barcoding for in vivo single-cell resolution analyses, we found that fetal liver definitive HSCs gave rise to both B-1a and B-2 cells. To directly assess whether a developmental shift in HSC state can lead to a selective loss in B-1a potential on a per cell basis, we performed longitudinal comparison of repopulation potential by following barcoded founder cells across serial transplantations. Whereas B-1a potential diminished over time, B-2 output was maintained. B-1a potential could be reinitiated in a subset of adult HSCs by ectopic expression of the RNA binding protein LIN28B, a key regulator of fetal hematopoiesis. This coincided with the clonal reversal to a fetal-like elevated self-renewal and repopulation potential. These results anchor the attenuation of B-1a cell output to fetal HSC behavior and demonstrate that the developmental decline in regenerative potential represents a reversible HSC state.
While these data made clear that developmentally restricted hematopoietic origins cannot fully account for the postnatal decline in B-1a output, the underlying mechanism for the positive selection and output of B-1a cells remains elusive. Recent studies showed that ectopic expression of Lin28b in adult pro-B cells was sufficient to potentiate fetal-like B-1a cell output. This led us to next hypothesize that Lin28b may play an important role during the latter part of B lymphopoiesis to potentiate the positive selection of B-1a cells early in life. We showed that CD5 levels of B-1 cells are developmentally set in the immature B cell stage and correlates with self-reactivity. Genetic perturbation studies show that Lin28b is necessary and sufficient for efficient positive selection of B-1a cells and potentiates neonatal immature B cell CD5 expression in a dose dependent fashion. Importantly, our results uncouple positive selection from specific B cell receptor identities, implicating the heterochronic RNA-binding protein LIN28b as the missing link that regulates the developmental attenuation in B-1a cell output through relaxing the permissiveness of B cell selection. Our findings shed light on the unique ability of B-1a cells to escape tolerance and undergo T cell like positive selection.
Finally, with ongoing investigations of developmental changes in chromatin accessibility between fetal and adult HSCs we have started to dissect the layers in regulation of a fetal HSC state. Interestingly, we find that regulation of the fetal HSC transcriptome relies more on a post-transcriptional layer compared to adult HSCs. This is consistent with the fetal specific expression pattern of the post-transcriptional regulator Lin28b.
Collectively this thesis work has elucidated fetal HSC state and Lin28b associated mechanisms in the attenuation of B-1a cell output during the transition from fetal to adult B lymphopoiesis.

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Keywords

  • B-1 B cells , Lin28, Fetal hematopoietic stem cells
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2018 May 24
Place of PublicationLund
Publisher
  • Lund University, Faculty of Medicine
Print ISBNs978-91-7619-639-7
Publication statusPublished - 2018
Publication categoryResearch

Bibliographic note

Defence details Date: 2018-05-24 Time: 09:00 Place: Segerfalksalen, BMC A10, Sölvegatan 17 i Lund External reviewer(s) Name: Cumano, Ana Title: professor Affiliation: Paris --- ISSN: 1652-8220 Lund University, Faculty of Medicine Doctoral Dissertation Series 2018:73

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