Biomedical subjects

Rosana Pelayo

Publications and source records attributed to Rosana Pelayo.

7 recordsLinked to original sources

PubMed2006

A novel human B cell subpopulation representing the initial germinal center population to express AID.

We have identified a novel mature human B-cell subpopulation in the human tonsil that has characteristics of both naive B cells and germinal center B cells including the expression of activation-induced cytidine deaminase (AID), which is essential for the process of immunoglobulin somatic hypermutation and class-switch recombination. These cells are clearly somatically hypermutated, albeit modestly. Their phenotype (IgD(+)CD38(-)CD23(-)FSC(hi)CD71(+)) is unique and suggests they may be intermediate between both naive and germinal center cells. Morphologically they are also distinct from other B-cell subpopulations. The evidence presented suggests these cells may be the founder cells of the germinal center reaction (a pro-GC cell) and may be the normal counterpart of the mantle cell lymphoma cell.

ADP-ribosyl Cyclase 1↗

PubMed2006

Cell cycle quiescence of early lymphoid progenitors in adult bone marrow.

Lymphocyte production in bone marrow (BM) requires substantial cell division, but the relationship between largely quiescent stem cells and dividing lymphoid progenitors is poorly understood. Therefore, the proliferation and cell cycle status of murine hematopoietic progenitors that have just initiated the lymphoid differentiation program represented the focus of this study. Continuous bromo-2'-deoxyuridine (BrdU) incorporation and DNA/RNA analysis by flow cytometry revealed that a surprisingly large fraction of RAG-1(+)c-kit(hi) early lymphoid progenitors (ELPs) and RAG-1(+)c-kit(lo) pro-lymphocytes (Pro-Ls) in adult BM were in cell cycle quiescence. In contrast, their counterparts in 14-day fetal liver actively proliferated. Indeed, the growth fraction (cells in G(1)-S-G(2)-M phases) of fetal ELPs was on average 80% versus only 30% for adult ELPs. After 5-fluorouracil treatment, as many as 60% of the adult ELP-enriched population was in G(1)-S-G(2)-M and 34% incorporated BrdU in 6 hours. Transcripts for Bcl-2, p21Cip1/Waf1, and p27 Kip1 cell cycle regulatory genes correlated inversely well with proliferative activity. Interestingly, adult lymphoid progenitors in rebound had the high potential for B lymphopoiesis in culture typical of their fetal counterparts. Thus, lymphocyte production is sustained during adult life by quiescent primitive progenitors that divide intermittently. Some, but not all, aspects of the fetal differentiation program are reacquired after chemotherapy.

Adult Stem Cells↗

PubMed2005

Life before the pre-B cell receptor checkpoint: specification and commitment of primitive lymphoid progenitors in adult bone marrow.

The production of B cells is a complex process determined by well-timed combinations of intrinsic factors and environmental cues that guide the differentiation of primitive progenitors in the bone marrow. Expression of several key transcription factors and receptor-stromal cell ligand interactions are landmarks of the earliest events in B lymphopoiesis in adult bone marrow. We describe this as a gradual loss of options for other blood cell lineages coincident with gain of essential properties. Experimental, stress or infection-related deregulation may change B cell fate specification, commitment or population dynamics, and consequently the production rate of mature populations.

Adult↗

PubMed2005

Propensity of adult lymphoid progenitors to progress to DN2/3 stage thymocytes with Notch receptor ligation.

Notch family receptors control critical events in the production and replenishment of specialized cells in the immune system. However, it is unclear whether Notch signaling regulates abrupt binary lineage choices in homogeneous progenitors or has more gradual influence over multiple aspects of the process. A recently developed coculture system with Delta 1-transduced stromal cells is being extensively used to address such fundamental questions. Different from fetal progenitors, multiple types of adult marrow cells expanded indefinitely in murine Delta-like 1-transduced OP9 cell cocultures, progressed to a DN2/DN3 thymocyte stage, and slowly produced TCR(+) and NK cells. Long-term cultured cells of this kind retained some potential for T lymphopoiesis in vivo. Adult marrow progressed through double-positive and single-positive stages only when IL-7 concentrations were low and passages were infrequent. Lin(-)c-Kit(low)GFP(+)IL-7Ralpha(+/-) prolymphocytes were the most efficient of adult bone marrow cells in short-term cultures, but the assay does not necessarily reflect cells normally responsible for replenishing the adult thymus. Although marrow-derived progenitors with Ig D(H)-J(H) rearrangements acquired T lineage characteristics in this model, that was not the case for more B committed cells with V(H)-D(H)J(H) rearrangement products.

Aging↗

PubMed2005

Derivation of 2 categories of plasmacytoid dendritic cells in murine bone marrow.

Plasmacytoid dendritic cells (pDCs) competent to make type I interferon were rigorously defined as a Ly-6C(+) and CD11c(Lo) subset of the B220(+)CD19(-) CD43(+)CD24(Lo) bone marrow (BM) Fraction A. Otherwise similar Ly6C(-) cells expressed the natural killer (NK) markers DX5 and NK1.1. pDCs represented a stable, discrete, and long-lived population. Stem cells and early lymphoid progenitors (ELPs), but not prolymphocytes, were effective precursors of pDCs, and their differentiation was blocked by ligation of Notch receptors. Furthermore, pDCs were present in the BM of RAG1(-/-), CD127/IL-7Ra(-/-), and Pax5(-/-) mice. pDCs in RAG1/GFP knock-in mice could be subdivided, and immunoglobulin D(H)-J(H) rearrangements, as well as transcripts for the B-lineage-related genes Pax5, mb1/CD79a, ebf, and Bcl11a, were identified only in the green fluorescent protein-positive (GFP(+)) pDC1 subset. All pDCs expressed terminal deoxynucleotidyl transferase (TdT), the ETS transcription factor Spi-B, the nuclear factor-kappaB transcription factor RelB, toll-like receptor 9 (TLR9), and interferon consensus sequence binding protein (ICSBP)/interferon regulatory factor 8 (IRF-8) transcripts; lacked CD16 and granulocyte colony-stimulating factor receptor (G-CSFR); and were uniformly interleukin-7 receptor alpha (IL-7Ralpha(-)) AA4.1(Lo), CD27(-), Flk-2(Lo), c-Kit(-), DX-5(-), and CD11b(-), while CD4 and CD8alpha were variable. GFP(+) pDC1 subset was less potent than GFP(-) pDC2s in T allostimulation and production of tumor necrosis factor alpha (TNFalpha), interferon alpha (IFNalpha), and interleukin-6 (IL-6), while only pDC2s made IFNgamma and IL-12 p70. Thus, 2 functionally specialized subsets of pDCs arise in bone marrow from progenitors that diverge from B, T, and NK lineages at an early stage.

Animals↗

PubMed2005

Lymphoid progenitors and primary routes to becoming cells of the immune system.

Extraordinary progress has been made in charting the maturation of hematopoietic cells. However, these charted processes do not necessarily represent obligate pathways to specialized types of lymphocytes. In fact, there is a degree of plasticity associated with primitive progenitors. Moreover, all lymphocytes of a given kind are not necessarily produced through precisely the same sequence of events. Particularly contentious is the nature of cells that seed the thymus, because different progenitors can generate T cells under experimental circumstances. Non-renewing progenitors with a high density of c-Kit in bone marrow are likely to replenish the thymus under normal circumstances and most closely resemble canonical T cell progenitors.

Animals↗

PubMed2004

Relationships between hematopoietic stem cells and lymphocyte progenitors.

Remarkable advances have been made in characterizing highly purified hematopoietic stem cells and their lymphoid progeny. The majority of the cytokines and cell interaction molecules that comprise their environment are probably known, as are most cell cycle regulatory proteins, signaling molecules and transcription factors that mediate the lineage fate decisions and control population dynamics. However, it is becoming obvious that traditional differentiation diagrams are not adequate for depicting early changes and give overly rigid impressions about how cells of the immune system arise.

Animals↗