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Functional and molecular analysis of B-lineage commitment suggests an instructive role for Il-7 in the earliest lymphoid restricted cells
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Deficiencies in the Il-7 signaling pathway result in severe disruptions of lymphoid development in adult mice. In order to understand how Il-7 deficiency impacts early lymphoid development we have investigated lineage restriction events within the CLP compartment of Il-7 knock out mice. This revealed that while Il-7 deficiency had a minor impact on the development and functional properties of LY6D- multipotent CLPs, the formation of the lineage restricted LY6D+ CLP population was dramatically reduced. This was reflected in a low level transcription of B-lineage genes as well as in a loss of functional B-cell commitment in developing progenitors. The defect could not be rescued by ectopic expression of Bcl-2 suggesting that the cytokine act in an instructive manner in early lymphoid development. This clarifies the role of Il-7 in early lymphoid development and puts emphasis on the relevance of the recently defined lineage restricted progenitor cells in lymphoid differentiation.

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-61589OAI: oai:DiVA.org:liu-61589DiVA: diva2:370520
Available from: 2010-11-17 Created: 2010-11-17 Last updated: 2010-11-17
In thesis
1. What’s in a name?: Sub-fractionation of common lymphoid progenitors
Open this publication in new window or tab >>What’s in a name?: Sub-fractionation of common lymphoid progenitors
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The hematopoietic system is a highly dynamic organ developed in many multi-cellular organisms to provide oxygen, prevent bleeding and to protect against microorganisms. The blood consist of many different specialized cells that all derive from rare hematopoietic stem cells (HSCs) located in the bone marrow in mice and humans. Blood cell production from HSCs occurs in a stepwise manner through development of intermediate progenitors that gradually loose lineage potentials. This is a tightly regulated process with complex regulatory mechanisms and many checkpoints that ensure a high and balanced production of blood cells. One of the fundamental questions in hematopoiesis relates to how the maturation of the cells is controlled and driven towards defined cell fates. The understanding of these processes is largely facilitated by isolation of intermediate populations of cells at defined stages of development.

This thesis is focused on the regulatory mechanisms that regulate the maturation of B-lymphocytes constituting an important part of adaptive immunity by being responsible for the production of antibodies. It has been suggested that all the lymphoid cells have a common lineage restricted ancestor defined as a Lin-KitloSca1loFlt3+IL7R+ common lymphoid progenitor (CLP). These cells are believed retain the combined potentials for B, T and NK cells and it has been presumed that commitment of CLPs to B lineage is associated with expression of CD19 and B220 on progenitor B-cells.

The aim of this thesis has been to identify the point of no return in B-cell development in order to allow for a better understanding of lineage restriction events in early lymphopoesis.

To this end, we have used reporter transgenic mice where marker gene expression has been controlled by the transcription regulatory elements from one early lymphoid marker (Rag1) and one B-lymphoid restricted gene (λ5, Igll1). This allowed us to identify three functionally distinct sub-populations within the conventional CLP compartment. The cells were identified as CLPRaglowλ5- cells retaining B, T, Nk and a limited myeloid potential while up-regulation of Rag1 to generate CLPRaghighλ5- cells, was associated with loss of Nk potential as well as of the residual myeloid potential. Ultimately expression of λ5 in the CLPRag1highλ5+ compartment identifies the first committed B cells. Hence, our data suggest that the point of no return in B-cell development can be found within the CD19- CLP compartment. Using this new model for B-cell development, we investigated the instructive vs. permissive role of IL7 signaling in B cell commitment. Our results show that in absence of IL7, CLP maturation is impaired and generation of the earliest committed B-lineage cells is severely impaired. CLP maturation could not be rescued by ectopic expression of the anti-apoptotic Bcl2 protein even though the cells were able to generate normal B lineage cells after restoration of the IL7 signal. These findings suggest that Il7 is crucial for the maturation of lineage restricted CLPs and provide support for an instructive role of IL7 in early Bcell development.

This thesis highlights the importance of precise identification of the point of commitment in B cell development and provides insight to the hematopoietic hierarchical model with the potential to serve as a map to better understand the mechanisms of hematopoietic disorders.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2010. 57 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1214
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-61590 (URN)978-91-7393-284-4 (ISBN)
Public defence
2010-11-29, Linden, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 13:00 (English)
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Available from: 2010-11-17 Created: 2010-11-17 Last updated: 2010-12-14Bibliographically approved

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Tsapogas, PanagiotisZandi, SasanÅhsberg, JosefineWelinder, EvaQian, HongSigvardsson, Mikael

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