Lin28b controls a neonatal to adult switch in B cell positive selection

Vanhee, Stiȷn; Åkerstrand, Hugo; Kristiansen, Trine A.; Datta, Sebak; Montano, Giorgia; Vergani, Stefano; Lang, Stefan; Ungerbäck, Jonas; Doyle, Alexander; Olsson, Karin; Beneventi, Giulia; Jensen, Christina T.; Bellodi, Cristian; Soneji, Shamit; Sigvardsson, Mikael; Gyllenbäck, Elin Jaensson; Yuan, Joan

doi:10.1126/sciimmunol.aax4453

Cited by 21 publications

(45 citation statements)

References 85 publications

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“…Since then, additional evidence from the lymphoid, erythroid, and megakaryocyte lineages has cemented the role of Lin28b as a molecular master switch for fetal hematopoiesis 28‐32 . In a recent study, we explored changes in B cell positive selection as a function of developmental timing 33 . Like in T cells, 34 we show that CD5 levels directly correlate with self‐reactivity in the mature B cell repertoire.…”

Section: A Molecular Switch Relaxes the Tolerance Threshold Early In mentioning

confidence: 84%

“…Interestingly, ectopic Lin28b in the adult was not sufficient to recapitulate the clonal dominance of the canonical VH11 and VH12 encoded PtC reactive public clonotypes. 32,33 Instead, B-1 cells licensed by Lin28b exhibit N-rich junctional diversity similar to that seen in the adult B cell repertoire. These results are in line with the fact that fetal lymphopoiesis takes place in the absence of terminal deoxynucleotidyl transferase (TdT) expression responsible for N nucleotide additions 36,37…”

Section: A Molecul Ar Switch Rel a Xe S The Toler An Ce Thre S Holdmentioning

confidence: 99%

“…[28][29][30][31][32] In a recent study, we explored changes in B cell positive selection as a function of developmental timing. 33 Like in T cells, 34 to self-antigen. 35 Together, these studies cement the role of Lin28b as a molecular switch for tuning the tolerance threshold during BCR repertoire selection early in life.…”

Section: A Molecul Ar Switch Rel a Xe S The Toler An Ce Thre S Holdmentioning

confidence: 99%

“…TdT expression in adult pro-B cells, 32,33 which dramatically increases the junctional diversity of the pre-selection repertoire compared to fetal lymphopoiesis. Thus, ectopic Lin28b in adult life allows for the incorporation of a more diverse pool of poly-and self-reactive B cells into the pre-immune repertoire compared to the fetal / neonatal set-…”

Section: And the Observation That Lin28b Does Not Abrogatementioning

confidence: 99%

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Developmental changes in the rules for B cell selection

Vergani

Yuan

2021

Immunological Reviews

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The autoimmune checkpoint during B cell maturation eliminates self-antigen reactive specificities from the mature B cell repertoire. However, an exception to this rule is illustrated by B-1 cells, an innate-like self-reactive B cell subset that is positively selected into the mature B cell pool in a self-antigen-driven fashion. The mechanisms by which B-1 cells escape central tolerance have puzzled the field for decades. A key clue comes from their restricted developmental window during fetal and neonatal life. Here we use B-1 cells as a prototypic early life derived B cell subset to explore developmental changes in the constraints of B cell selection. We discuss recent advancements in the understanding of the molecular program, centered around the RNA binding protein Lin28b, that licenses self-reactive B-1 cell output during ontogeny. Finally, we speculate on the possible link between the unique rules of early life B cell tolerance and the establishment of B cell-microbial mutualism to propose an integrated model for how developmental and environmental cues come together to create a protective layer of B cell memory involved in neonatal immune imprinting.

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Section: A Molecular Switch Relaxes the Tolerance Threshold Early In mentioning

confidence: 84%

Section: A Molecul Ar Switch Rel a Xe S The Toler An Ce Thre S Holdmentioning

confidence: 99%

Section: A Molecul Ar Switch Rel a Xe S The Toler An Ce Thre S Holdmentioning

confidence: 99%

Section: And the Observation That Lin28b Does Not Abrogatementioning

confidence: 99%

See 2 more Smart Citations

Developmental changes in the rules for B cell selection

Vergani

Yuan

2021

Immunological Reviews

Self Cite

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“…Moreover, it was recently shown that antigen receptor specificity is sufficient to induce cell proliferation and acquisition of the B-1 phenotype and function (Graf et al, 2019). Lin28b, a regulator of fetal hematopoiesis, is important in the generation of B1a lineage, and loss of its expression controls the switch from neonatal to adult B cell production (Vanhee et al, 2019). Low levels of IL-7, a cytokine crucial for adult B cell development, in FL favors the generation of B1, highlighting the impact of the microenvironment on the preferential production of particular cell types (Wong et al, 2019).…”

Section: B Cell Developmentmentioning

confidence: 99%

Hematopoiesis: A Layered Organization Across Chordate Species

Elsaid

Soares-da-Silva

Peixoto

et al. 2020

Front. Cell Dev. Biol.

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The identification of distinct waves of progenitors during development, each corresponding to a specific time, space, and function, provided the basis for the concept of a “layered” organization in development. The concept of a layered hematopoiesis was established by classical embryology studies in birds and amphibians. Recent progress in generating reliable lineage tracing models together with transcriptional and proteomic analyses in single cells revealed that, also in mammals, the hematopoietic system evolves in successive waves of progenitors with distinct properties and fate. During embryogenesis, sequential waves of hematopoietic progenitors emerge at different anatomic sites, generating specific cell types with distinct functions and tissue homing capacities. The first progenitors originate in the yolk sac before the emergence of hematopoietic stem cells, some giving rise to progenies that persist throughout life. Hematopoietic stem cell-derived cells that protect organisms against environmental pathogens follow the same sequential strategy, with subsets of lymphoid cells being only produced during embryonic development. Growing evidence indicates that fetal immune cells contribute to the proper development of the organs they seed and later ensure life-long tissue homeostasis and immune protection. They include macrophages, mast cells, some γδ T cells, B-1 B cells, and innate lymphoid cells, which have “non-redundant” functions, and early perturbations in their development or function affect immunity in the adult. These observations challenged the view that all hematopoietic cells found in the adult result from constant and monotonous production from bone marrow-resident hematopoietic stem cells. In this review, we evaluate evidence for a layered hematopoietic system across species. We discuss mechanisms and selective pressures leading to the temporal generation of different cell types. We elaborate on the consequences of disturbing fetal immune cells on tissue homeostasis and immune development later in life.

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Insights into B‐cell ontogeny inferred from human immunology

et al. 2023

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Due to ontogenetic changes in B‐cell developmental lineages, the mature B‐cell compartment constitutes by functionally different B‐cell subsets that emerged from prenatal, early postnatal or adult precursors. While negative selection processes operate primarily within the framework of B‐cell tolerance checkpoints during B‐cell development, further differentiation into distinct B‐cell subsets is additionally induced by positive selection. In addition to endogenous antigens, contact with microbial antigens is also involved in this selection process, with intestinal commensals having a significant influence on the development of a large layer within the B‐cell compartment. The decisive threshold that triggers negative selection seems to be relaxed during fetal B‐cell development, thereby allowing recruitment of polyreactive and also autoreactive B‐cell clones into the mature naïve B‐cell compartment. Almost all of the concepts on B‐cell ontogeny are based on observations in laboratory mice that not only differ from humans in their developmental timeline but also in their composition of commensal microorganisms or rather a lack of exposure to these. In this review, we summarize conceptual findings on B‐cell ontogeny and particularly describe key insights into the developing human B‐cell compartment and immunoglobulin repertoire formation.

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Lin28b controls a neonatal to adult switch in B cell positive selection

Cited by 21 publications

References 85 publications

Developmental changes in the rules for B cell selection

Developmental changes in the rules for B cell selection

Hematopoiesis: A Layered Organization Across Chordate Species

Insights into B‐cell ontogeny inferred from human immunology

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