The Dielmo project, initiated in 1990, consisted of long-term investigations on host-parasite relationships and the mechanisms of protective immunity in the 247 residents of a Senegalese village in which malaria is holoendemic. Anopheles gambiae s.1. and An. funestus constituted more than 98% of 11,685 anophelines collected and were present all year round. Inoculation rates of Plasmodium falciparum, P. malariae, and P. ovale averaged respectively 0.51, 0.10, and 0.04 infective bites per person per night. During a four-month period of intensive parasitologic and clinical monitoring, Plasmodium falciparum, P. malariae, and P. ovale were observed in 72.0%, 21.1% and 6.0%, respectively, of the 8,539 thick smears examined. Individual longitudinal data revealed that 98.6% of the villagers harbored trophozoites of P. falciparum at least once during the period of the study. Infections by P. malariae and P. ovale were both observed in individuals of all age groups and their cumulative prevalences reached 50.5% and 40.3%, Î-espectively. Malaria was responsible for 162 (60.9%) of 266 febrile episodes; 159 of these attacks were due to P. falciparum, three to P. ovale, and none to P. malariae. The incidence of malaria attacks was 40 times higher in children 0-4 years of age than in adults more than 40 years old. Our findings suggest that sterile immunity and clinical protection are never fully achieved in humans continuously exposed since birth to intense transmission.
The early stages of human lymphopoiesis are poorly characterized. Here, we compared the lymphoid potential of a novel umbilical cord blood CD34 ؉ CD45RA hi CD7 ؉ hematopoietic progenitor cell (HPC) population with that of CD34 ؉ CD45RA hi Lin ؊ CD10 ؉ HPCs, previously proposed as candidate common lymphoid progenitors. Limitingdilution and clonal analysis, fetal thymic organ cultures, and culture onto Notch ligand Delta-like-1-expressing OP9 cells, showed that although CD34 ؉ CD45RA hi CD7 ؉ HPCs could generate cells of the 3 lymphoid lineages, their potential was skewed toward the T/natural killer (T/NK) lineages. In contrast, CD34 ؉ CD45RA hi Lin ؊ CD10 ؉ HPCs predominantly exhibited a B-cell potential. Gene expression profiling with DNA microarrays confirmed that CD34 ؉ CD45RA hi CD7 ؉ HPCs selectively expressed T-lymphoid and NK lineage-committed genes while retaining expression of genes affiliated to the granulomonocytic lineage, whereas CD34 ؉ CD45RA hi Lin ؊ CD10 ؉ HPCs displayed a typical pro-B-cell transcription profile and essentially lacked genes unrelated to the B lineage. In addition, both populations could be generated in vitro from CD34 ؉ CD45RA int CD7 ؊ and CD34 ؉ CD45RA hi Lin ؊ HPCs with mixed lymphomyeloid potential, from which they emerged independently with different growth/ differentiation factor requirements. These findings indicate that CD34 ؉ CD45RA hi CD7 ؉ and CD34 ؉ CD45RA hi Lin ؊ CD10 ؉ HPCs correspond to multipotent early lymphoid progenitors polarized toward either the T/NK or B lineage, respectively. IntroductionThe immediate progeny of pluripotent hematopoietic stem cells is thought to correspond to common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs). CMPs are assumed to give rise to granulocytes and macrophages, as well as to the erythroid and megakaryocytic lineages, whereas CLPs are committed to generate either B lymphocytes (BLs) or T lymphocytes (TLs) and natural killer (NK) cells. 1,2 Evidence for a primary segregation between CLPs and CMPs stems from in vivo transfer experiments in adult mice, where 2 populations of c-Kit lo Sca lo IL-7R ϩ and Fc␥R lo CD34 ϩ hematopoietic progenitor cells (HPCs) isolated from the postnatal bone marrow (BM) were shown to selectively reconstitute either the lymphoid 3 or erythromegakaryocytic and granulomonocytic lineages. 4 Such a dichotomous model of hematopoiesis remains however debated because there is also evidence that multilineage precursors coexpress lymphoid as well as myeloerythroid genes [5][6][7] and that populations of early lymphoid progenitors (ELPs) retain some degree of multipotency. [8][9][10][11] For example, AA4.1 ϩ Fc␥R ϩ fetal precursors with TL and BL potential retain significant macrophage potential but fail to generate erythroid or granulocytic cells. 8 In line with these findings, early GFP lo c-kit hi Sca-1 ϩ BL precursors from RAG1/GFP (recombination activating gene 1/green fluorescent protein) knock-in mice still express TL and macrophage potential when cultured under appropriate conditions...
The C-type lectin DC-SIGN expressed on immature dendritic cells (DCs) captures human immunodeficiency virus (HIV) particles and enhances the infection of CD4؉ T cells. This process, known as trans-enhancement of T-cell infection, has been related to HIV endocytosis. It has been proposed that DC-SIGN targets HIV to a nondegradative compartment within DCs and DC-SIGN-expressing cells, allowing incoming virus to persist for several days before infecting target cells. In this study, we provide several lines of evidence suggesting that intracellular storage of intact virions does not contribute to HIV transmission. We show that endocytosis-defective DC-SIGN molecules enhance T-cell infection as efficiently as their wild-type counterparts, indicating that DC-SIGN-mediated HIV internalization is dispensable for trans-enhancement. Furthermore, using immature DCs that are genetically resistant to infection, we demonstrate that several days after viral uptake, HIV transfer from DCs to T cells requires viral fusion and occurs exclusively through DC infection and transmission of newly synthesized viral particles. Importantly, our results suggest that DC-SIGN participates in this process by cooperating with the HIV entry receptors to facilitate cis-infection of immature DCs and subsequent viral transfer to T cells. We suggest that such a mechanism, rather than intracellular storage of incoming virus, accounts for the long-term transfer of HIV to CD4 ؉ T cells and may contribute to the spread of infection by DCs.
Here, we identify fetal bone marrow (BM)-derived CD34hiCD45RAhiCD7+ hematopoietic progenitors as thymus-colonizing cells. This population, virtually absent from the fetal liver (FL), emerges in the BM by development weeks 8-9, where it accumulates throughout the second trimester, to finally decline around birth. Based on phenotypic, molecular, and functional criteria, we demonstrate that CD34hiCD45RAhiCD7+ cells represent the direct precursors of the most immature CD34hiCD1a- fetal thymocytes that follow a similar dynamics pattern during fetal and early postnatal development. Histological analysis of fetal thymuses further reveals that early immigrants predominantly localize in the perivascular areas of the cortex, where they form a lymphostromal complex with thymic epithelial cells (TECs) driving their rapid specification toward the T lineage. Finally, using an ex vivo xenogeneic thymus-colonization assay, we show that BM-derived CD34hiCD45RAhiCD7+ progenitors are selectively recruited into the thymus parenchyma in the absence of exogenous cytokines, where they adopt a definitive T cell fate.
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