Increasing Flt3L availability alters composition of a novel bone marrow lymphoid progenitor compartment.

International audienceWe have recently described a CD19(-) B220(+)CD117(low) bone marrow subpopulation with B, T, and myeloid developmental potential, which we have called "early progenitors with lymphoid and myeloid potential" or EPLM. These cells also expressed Fms-like tyrosine kinase 3, Flt3, or CD135. Treatment of mice with the corresponding ligand, Flt3L, showed a 50-fold increase in EPLM. In addition to the expected increase in dendritic cell numbers, Flt3L treatment had a reversible inhibitory effect on B lymphopoiesis. Limiting dilution analysis of sorted EPLM from Flt3L-treated mice showed that B-lymphocyte progenitor activity was reduced 20-fold, but that myeloid and T-cell progenitor activity was largely preserved. EPLM from treated mice transiently reconstituted the thymus and bone marrow of recipient mice, generating cohorts of functional T and B cells in peripheral lymphoid organs. Thus, Flt3L treatment results in a dramatic increase in a novel bone marrow cell with lymphoid and myeloid progenitor activity

Critical role for c-kit (CD117) in T cell lineage commitment and early thymocyte development in vitro.

International audienceThe precise roles played by the transmembrane receptor tyrosine kinase c-kit and its ligand stem cell factor in early T cell development are difficult to study. Using cloned Pax5-deficient progenitor B cells, we show that following Notch signaling, which induces their commitment to the T cell developmental pathway, c-kit expression is rapidly up-regulated at both the transcriptional and cell surface level. Using either an anti-c-kit monoclonal antibody or Gleevec, a pharmacological inhibitor of c-kit signaling, we show that the Notch-induced T cell differentiation of either Pax5-deficient progenitor B cells, or the equivalent cell from the bone marrow of normal mice, is strictly dependent on c-kit signaling, whereas the differentiation of normal progenitors into the B cell lineage is not. Moreover, we show that the Notch and IL-7 signaling-induced proliferation and differentiation of CD44+CD25-c-kit(high) and CD44+CD25+c-kithigh thymocytes along the T cell, but not natural killer cell or macrophage, pathway also requires c-kit signaling, whereas the Notch-induced proliferation and differentiation of CD44-CD25+c-kitint cells along the T cell pathway is independent of c-kit. These results further highlight the complex inter-relationships existing between c-kit, Notch and IL-7 receptor signaling that control the proliferation and differentiation of early T cell progenitors

The potential involvement of Notch signaling in NK cell development.

International audienceNK cells constitute an essential element of the innate immune system; however, the cellular and molecular mechanisms that guide their early development are still poorly understood. Here, we demonstrate that in addition to its known crucial role in T cell development, Notch signaling can also be involved in NK cell development. Thus, upon co-culture on OP9 stroma expressing the Notch ligand Delta-like 1 (OP9-DL1), Pax5-deficient pro-B cells, which have multi-lineage potential, efficiently differentiate into T and NK cells. Upon DL-1 signaling, Pax5-deficient pro-B cells down-regulate both surface CD93 expression and transcripts for B cell-specific genes and concomitantly up-regulate T lineage gene transcripts. Subsequent transfer of DL-1-signaled Pax5-deficient pro-B cells onto OP9 stroma in the presence of IL-2 leads to their efficient differentiation into NK1.1(+), functional NK cells. Moreover, bone marrow early progenitor with lymphoid and myeloid differentiation potential (EPLM), which we have previously described as the normal in vivo-equivalent of Pax5-deficient pro-B cells, also gain the ability to differentiate into effector NK cells following transient DL1 Notch-mediated signaling. The potential involvement of Notch signaling in the generation of the NK cell repertoire in vivo is discussed

Hepatitis C in Lithuania: incidence, prevalence, risk factors and viral genotypes

BACKGROUND: The epidemiology of hepatitis C virus (HCV) infection has been studied in many countries. However, little is known about HCV infection in Lithuania, a Baltic country, that was part of the former Soviet Union. OBJECTIVES: The aim of this study was to determine and evaluate the etiology of acute viral hepatitis, the risk factors for acquiring HCV in comparison to hepatitis B virus (HBV), seroprevalence of anti-HCV among blood donors and risk groups of the population in Lithuania. The distribution of HCV genotypes from Lithuanian first-time blood donors was also assessed. STUDY DESIGN: Sera taken from clinical viral hepatitis patients, blood donors, risk groups of population were investigated serologically. Patients with acute viral hepatitis were interviewed to determine their risk factors for HCV and HBV. HCV genotyping was done by PCR using type specific primers. RESULTS: Acute hepatitis C accounted for 5.0-8.5% of reported viral hepatitis cases in adults in Vilnius. Of the acute hepatitis C cases, 37.0% was associated with blood transfusions before the implementation of screening of blood donors for anti-HCV and only 15.4% (2/13) after the screening was started. Anti-HCV was found in 2.2% of first-time blood donors, in 7.9% of commercial blood donors, in 13.9% of commercial blood plasma donors, in 48.3% of hemodialysis patients, in 29.4% of prisoners, in 9.4% of elderly nursing home residents, and in 7.9% of hemodialysis staff. The following distribution in genotypes were found: genotype 1b (54.3%), 3a (23.9%), 2a (10.9%) 2b (4.3%), 1a (0%), and double infection (6.5%). CONCLUSIONS: Lithuania is a country with a considerable hepatitis C problem

Early lymphocyte development in bone marrow and thymus.

Free Full Text : http://www.smw.ch/docs/pdf200x/2006/4/smw-11413.pdfInternational audienceHaematopoietic stem cells (HSCs), a very rare cell type in the bone marrow, are responsible for the life-long production of all cells of the blood including T and B cells. Until recently, it was thought that the differentiation of HSCs into the various haematopoietic cells was rather hierarchical in that differentiation along a given lineage was associated with a progressive loss of potential to give rise to other blood cell lineages. The recent development of very sensitive and quantitative in vitro assays, together with the identification of new progenitor subpopulations, has challenged this idea. Thus, lymphocyte progenitors can be shown to keep their developmental potential to give rise to myeloid, dendritic and NK cells until just prior to their final commitment stage. Here we review these new findings and concepts