Sadly, Prof. Antonius Rolink passed away on August 6, 2017.

Hematopoiesis . B Cell Development . T Cell Development . IL-7 and Autoimmunity

Molecular mechanisms guiding hematopoietic cell development

A permissive role for IL-7 in mouse B cell development
Patients deficient for IL-7 or the IL-7R are practically devoid of T cells but have normalB cell compartments. In mice deficient for IL-7 or the IL-7R both T cell and B cell compartments are dramatically reduced. Based on these findings it was argued that IL-7 plays a redundant role in human B cell development but a non-redundant and may be even an instructive role in mouse B cell development. Now we challenged this hypothesis by analyzing the by us generated FLT3L transgenic mice. These transgenic mice posses dramatically increased populations of progenitor cells in the bone marrow including the pre-pro-B cells. Now by generatingIL-7 deficient mice on a FLT3L transgenic background we found a very significant rescue of all the precursor B cell subpopulations in the bone marrow and the matureB cell populations in the periphery. Thus, increased levels of FLT3L make the role of IL-7 in mouse B cell development largely redundant. Our findings rather suggest that IL-7 mainly acts as a growth factor for pre-B cells and thereby making B cell development more efficient. Yet, another suggestion coming from our studies is that human B cell development is regulated by FLT3L.

Hematopoietic progenitors with multipotent developmental potential:real multipotency or heterogeneity?
Over the past couple of years new hematopoietic progenitors with multipotent developmental potential mainly determined in vitro were described. However, by the generation of so-called reporter mice the multipotency of some of these precursors in vivo was questioned. Moreover, the multipotent developmental potential in vitro of these precursors was tested at the “bulk” but not at the single cell level.Therefore, the in vivo significance of this multipotency is questionable and furthermore the in vitro experiments do not exclude heterogeneity within the tested precursor populations.
Several years ago we have described a small bone marrow derived precursor populationwith lymphoid and myeloid developmental potential in vitro (Balciunaite G,Ceredig R, Massa S, Rolink AG. Eur J Immunol. 2005 Jul;35(7):2019-30). This populationcomprises 0.1 – 0.3% of total BM nucleated cells and was characterized asbeing B220+ c-Kit+ CD19- NK1.1-. Now, by identifying new markers and by analyzingnewly generated mutant mice we have found that this population can be subdividedinto at least 6 subpopulations. The main marker we used for this was Ly6D.Single cell RNA- sequence analysis performed on the Ly6D+ and Ly6D-, B220+ c-Kit+ CD19- NK1.1- cells revealed within the Ly6D+ cells a largely lymphoid restrictedtranscriptome whereas the Ly6D- cells showed either a transcriptome reminiscentof lymphoid, myeloid or dendritic cells. Thus these findings reveal that B220+c-Kit+ CD19- NK1.1- cells are very heterogeneous and that myeloid and lymphoiddevelopmental potential is coming from different cells within this population.

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