Periodic Reporting for period 4 - FatemapB (High Resolution Mapping of Fetal and Adult B Cell Fates During Ontogeny)
Período documentado: 2022-04-01 hasta 2022-09-30
FateMapB aims to understand how the unique differentiation potential of fetal hematopoietic stem and progenitor cells (HSPCs) contribute to functionally distinct B cell types of the adult immune system. While most immune cells are replenished by HSPCs through life, others emerge during a limited window early in life and sustain through self-maintenance. The extent to which early life derived antibody producing B cell output contributes to the adult B cell repertoire remain unclear. I previously identified the fetal specific RNA binding protein Lin28b as a post-transcriptional molecular switch capable of inducing fetal-like hematopoiesis in adult bone marrow HSPCs. This discovery has afforded me with unique perspectives on the formation of the mammalian adaptive immune system. The concept that the adult B cell compartment is a mosaic of fetal and adult derived cell types is addressed in this proposal. We are using two complementary lineage-tracing technologies to stratify the immune system as a function of developmental time, generating fundamental insight into the age specific features of fetal and adult HSPCs that ultimately provides a functional division of labor within the adult B cell repertoire and effective humoral immunity.
The overall objectives of FatemapB are as follows:
Aim 1. Determine the quantitative and qualitative contribution of early life B cell output to the adult B cell pool through ‘time stamping’.
Aim 2. Resolve the developmental relationship between fetal and adult derived B cells by single cell lineage-tracing.
Aim 3. Characterize the basis for and immune functions of induced fetal-like B cell output from adult HSPCs.
The societal impact of FateMapB extends beyond academic understanding of the formation of a diverse immune system to implications amenable for clinical exploitation within the areas of immune regeneration, neonatal immune imprinting and the development and optimization of vaccination strategies.
The overall objectives of FatemapB are as follows:
Aim 1. Determine the quantitative and qualitative contribution of early life B cell output to the adult B cell pool through ‘time stamping’.
Aim 2. Resolve the developmental relationship between fetal and adult derived B cells by single cell lineage-tracing.
Aim 3. Characterize the basis for and immune functions of induced fetal-like B cell output from adult HSPCs.
The societal impact of FateMapB extends beyond academic understanding of the formation of a diverse immune system to implications amenable for clinical exploitation within the areas of immune regeneration, neonatal immune imprinting and the development and optimization of vaccination strategies.
By time-stamping B cells that arise early in life, we have successfully resolved a self-sustaining network of early life B cell memory. These early life origin B (ELO-B) cells are unevenly distributed among immunophenotypically and anatomically defined B cell subsets and make up a substantial portion of the adult B cell pool in unimmunized mice accounting for nearly half of all IgM and IgA plasma cells. Our findings reveal pervasive neonatal antigenic imprinting of the adult B cell compartment challenging the assumption that adaptive immune system is naïve in the absence of deliberate immunization. These findings provide a new conceptual framework for deconvoluting B cell responses in health and disease. Their publication the journal Immunity in 2022 and marks the successful delivery of the number one objective of FateMapB.
In addition we have demonstrated that the developmentally restricted expression of Lin28b temporarily relaxes the autoimmune checkpoint during B cell development allowing for augmented B cell positive selection and peripheral output (Science Immunology 2019). Thus, Lin28b breeches the censorship of developing B cells with perceived self-antigen engagement and the output of poly-reactive B-1 cells early in life. Furthermore, ectopic Lin28b expression in adult B cell precursors reinitiates the fetal-like augmented state of positive selection. The latter was quantified using cellular barcoding, a single cell lineage tracing method allowing for the relative quantification of precursor-progeny ratio of pre- and post-selection B cells in vivo. We propose that this neonatal mode of B cell selection represents a cell intrinsic cue to accelerate the de novo establishment of the adaptive immune system and incorporate a layer of natural antibody mediated immunity throughout life.
In addition we have demonstrated that the developmentally restricted expression of Lin28b temporarily relaxes the autoimmune checkpoint during B cell development allowing for augmented B cell positive selection and peripheral output (Science Immunology 2019). Thus, Lin28b breeches the censorship of developing B cells with perceived self-antigen engagement and the output of poly-reactive B-1 cells early in life. Furthermore, ectopic Lin28b expression in adult B cell precursors reinitiates the fetal-like augmented state of positive selection. The latter was quantified using cellular barcoding, a single cell lineage tracing method allowing for the relative quantification of precursor-progeny ratio of pre- and post-selection B cells in vivo. We propose that this neonatal mode of B cell selection represents a cell intrinsic cue to accelerate the de novo establishment of the adaptive immune system and incorporate a layer of natural antibody mediated immunity throughout life.
In the discipline of experimental B cell immunology, the conventional starting point for experimental observations begins just upon antigenic challenge in unperturbed adult mice. The assumption is that the adaptive immune system is naïve in the absence of deliberate immunization. The findings of FatemapB challenge this general assumption and highlights the importance of naturally occurring neonatal priming. These findings call for future investigations dedicated to understanding how neonatal B cell memory contributes to, or feeds back on, adult immune responses in health and disease.
Our research has also demonstrated the ability of Lin28b to relax the autoimmune checkpoint to augment positive selection and overall B cell output early in life. Lin28b therefore offers a potential mechanism to explain the long-known fact that neonatal B cells are frequently self-reactive in mice and men. Of particular interest is the timing of Lin28b expression which in mice lasts until the third week of life. This overlaps with the immune formative event of weaning associated gut microbial colonisation, and offers an attractive possible explanation to the time-limited effects of neonatal exposure that cannot be recapitulated later in life.
Our research has also demonstrated the ability of Lin28b to relax the autoimmune checkpoint to augment positive selection and overall B cell output early in life. Lin28b therefore offers a potential mechanism to explain the long-known fact that neonatal B cells are frequently self-reactive in mice and men. Of particular interest is the timing of Lin28b expression which in mice lasts until the third week of life. This overlaps with the immune formative event of weaning associated gut microbial colonisation, and offers an attractive possible explanation to the time-limited effects of neonatal exposure that cannot be recapitulated later in life.