Correction: Kinetics of In Vivo Proliferation and Death of Memory and Naive CD8 Cells: Parameter Estimation Based on 5-Bromo-2′-Deoxyuridine Incorporation in Spleen, Lymph Nodes, and Bone Marrow

Abstract By comparing mature CD8-cell turnover in different organs, we previously demonstrated that CD8 cells proliferate predominantly in the bone marrow (BM). To investigate the mechanisms underlying such increased turnover, we compared BM, lymph nodes, and spleen CD8 cells from untreated C57BL/6 mice regarding in vivo proliferation within the organ; in vitro response to interleukin-7 (IL-7), IL-15, IL-21; ex vivo expression of membrane CD127 (IL-7Rα), intracellular Bcl-2, phospho–STAT-5 (signal transducer and activator of transcription 5), phospho-p38 mitogen activated protein kinase (MAPK); and in vivo proliferation on adoptive transfer. In the BM, the proliferation rate was increased for either total CD8 cells or individual CD44 and CD122 subsets. In contrast, purified CD8+ cells from the BM did not show an enhanced in vitro proliferative response to IL-7, IL-15, and IL-21 compared with corresponding spleen cells. After transfer and polyinosinic-polycytidylic acid (polyI:C) treatment, both spleen-derived and BM-derived CD8 cells from congenic donors proliferated approximately twice more in the recipient BM than in spleen and lymph nodes. Our results suggest that BM CD8 cells are not committed to self-renewal, but rather are stimulated in the organ. Molecular events constantly induced in the CD8 cells within the BM of untreated mice include increase of both phosphorylated STAT-5 and phosphorylated p38 intracellular levels, and the reduction of CD127 membrane expression.

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Eosinophilia in transgenic mice expressing interleukin 5.

Journal of Experimental Medicine ◽

10.1084/jem.172.5.1425 ◽

1990 ◽

Vol 172 (5) ◽

pp. 1425-1431 ◽

Cited By ~ 392

Author(s):

L A Dent ◽

M Strath ◽

A L Mellor ◽

C J Sanderson

Keyword(s):

Bone Marrow ◽

Transgenic Mice ◽

Lymph Nodes ◽

Peyer's Patches ◽

Peyer’S Patches ◽

Mesenteric Lymph Nodes ◽

Gene Encoding ◽

Interleukin 5

Experiments in vitro suggest that although interleukin 5 (IL-5) stimulates the late stages of eosinophil differentiation, other cytokines are required for the generation of eosinophil progenitor cells. In this study transgenic mice constitutively expressing the IL-5 gene were established using a genomic fragment of the IL-5 gene coupled to the dominant control region from the gene encoding human CD2. Four independent eosinophilic transgenic lines have thus far been established, two of which with 8 and 49 transgene copies, are described in detail. These mice appeared macroscopically normal apart from splenomegaly. Eosinophils were at least 65- and 265-fold higher in blood from transgenics, relative to normal littermates, and approximately two- or sevenfold more numerous relative to blood from mice infected with the helminth Mesocestoides corti. Much more modest increases in blood neutrophil, lymphocyte, and monocyte numbers were noted in transgenics, relative to normal littermates (less than threefold). Thus IL-5 in vivo is relatively specific for the eosinophil lineage. Large numbers of eosinophils were present in spleen, bone marrow, and peritoneal exudate, and were highest in the line with the greatest transgene copy number. Eosinophilia was also noted in histological sections of transgenic lungs, Peyer's patches, mesenteric lymph nodes, and gut lamina propria but not in other tissues examined. IL-5 was detected in the sera of transgenics at levels comparable to those seen in sera from parasite-infected animals. IL-3 and granulocyte/macrophage colony-stimulating factor (GM-CSF) were not found. IL-5 mRNA was detected in transgenic thymus, Peyer's patches, and superficial lymph nodes, but not in heart, liver, brain, or skeletal muscle or in any tissues from nontransgenics. Bone marrow from transgenic mice was rich in IL-5-dependent eosinophil precursors. These data indicate that induction of the IL-5 gene is sufficient for production of eosinophilia, and that IL-5 can induce the full pathway of eosinophil differentiation. IL-5 may therefore not be restricted in action to the later stages of eosinophil differentiation, as suggested by earlier in vitro studies.

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The Kinetics of the Normal, the Megaloblastic and the Sideroachrestic Erythropoiesis Estimated by Colchicine Blocking In Vitro

Blood ◽

10.1182/blood.v37.2.204.204 ◽

1971 ◽

Vol 37 (2) ◽

pp. 204-210 ◽

Cited By ~ 5

Author(s):

I. T. M. BOLL ◽

H.-P. KOENIGS

Keyword(s):

Bone Marrow ◽

Maturation Stage ◽

Ineffective Erythropoiesis ◽

Cell Doubling Time ◽

Bone Marrow Cultures ◽

Delayed Maturation ◽

Kinetics Of ◽

Very High

Abstract By adding colchicine to bone marrow cultures we developed further parameters for kinetics in normal, megaloblastic and sideroachrestic bone marrow. The increased regeneration in megalopoiesis is demonstrated by an increased mitotic index, an increased stathmokinetic index, a shortened cell doubling time and the prolongation of the divisable pool to the oxyphile erythroblasts which only mature in the normal state. To get ineffective erythropoiesis, the maturation in vivo must have been delayed by an increased number of generations up to the formation of megalocytes. From the stathmokinetic test in vitro, the maturation in megalopoiesis is accelerated as a result of the inhibition of α-2 α-divisions. In normal erythropoiesis stopping mitoses by colchicine probably causes a delayed maturation because the next maturation stage cannot be reached without the regular n-2n-division. In sideroachrestic anemia, the maturation behaves normally but the stathmokinetic test is very high. We conclude that the maturation and mode of division in sideroachrestic anemia is nearly normal.

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Direct in vivo evidence for increased proliferation of CLL cells in lymph nodes compared to bone marrow and peripheral blood

Leukemia ◽

10.1038/leu.2017.11 ◽

2017 ◽

Vol 31 (6) ◽

pp. 1340-1347 ◽

Cited By ~ 37

Author(s):

T M Herndon ◽

S-S Chen ◽

N S Saba ◽

J Valdez ◽

C Emson ◽

...

Keyword(s):

Bone Marrow ◽

Lymph Nodes ◽

Peripheral Blood

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The kinetics of in vivo sister chromatid exchange induction in mouse bone marrow cells by alkylating agents: Cyclophosphamide

Environmental Mutagenesis ◽

10.1002/em.2860050607 ◽

1983 ◽

Vol 5 (6) ◽

pp. 825-834 ◽

Cited By ~ 8

Author(s):

James L. Charles ◽

David Jacobson-Kram ◽

Joseph F. Borzelleca ◽

Richard A. Carchman

Keyword(s):

Bone Marrow ◽

Sister Chromatid ◽

Sister Chromatid Exchange ◽

Bone Marrow Cells ◽

Alkylating Agents ◽

Mouse Bone Marrow ◽

Kinetics Of ◽

Mouse Bone Marrow Cells ◽

Marrow Cells

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Heterologous cells cooperate to augment stem cell migration, homing, and engraftment

Blood ◽

10.1182/blood-2002-02-0486 ◽

2003 ◽

Vol 101 (1) ◽

pp. 45-51 ◽

Cited By ~ 37

Author(s):

Gregor B. Adams ◽

Karissa T. Chabner ◽

Russell B. Foxall ◽

Kathryn W. Weibrecht ◽

Neil P. Rodrigues ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Cell Migration ◽

Severe Combined Immunodeficiency ◽

Host Cells ◽

Alternative Mechanism ◽

Cell Homing ◽

Cd8 Cells ◽

Cd34 Cells

Abstract T-lymphocyte depletion of bone marrow grafts compromises engraftment, suggesting a facilitating mechanism provided by the T cells that has been shown to associate with CD8+ but not CD4+ T cells. Explanations for this phenomenon have focused on immune targeting of residual host cells or cytokine production. We provide evidence for an alternative mechanism based on cooperative effects on cell motility. We observed that engraftment of CD34+ cells in a β2-microglobulin–deficient nonobese diabetic/severe combined immunodeficiency (β2m−/− NOD/SCID) mouse model paralleled clinical observations in humans, with an enhancing effect noted from the addition of CD8+ cells but not CD4+ cells. This correlated with CD8+ augmentation of CD34+cell homing to the bone marrow in vivo and CD8+cell–associated increases of CD34+ cell transmigration through a bone marrow endothelial cell line in vitro. The cooperative interaction was not sensitive to brefeldin A inhibition of protein secretion. However, cytochalasin D–induced inhibition of CD8+ cytoskeletal rearrangements abrogated CD34+ transendothelial migration and impaired CD34+ cell homing in vivo. CD8+ cells did not migrate in tandem with CD34+ cells or alter endothelial barrier integrity; rather, they affected phosphotyrosine-mediated signaling in CD34+ cells in response to the chemokine stromal derived factor-1α (SDF-1α). These data demonstrate cell-cell cooperativity between different cell types in mediating chemotactic events and provide one potential explanation for the clinically observed effect of CD8+ cells on bone marrow transplantation. This modification of cell migration by neighboring cells provides broad possibilities for combinatorial effects between cells of different types to influence cell localization.

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Multiple extrathymic precursors contribute to T-cell development with different kinetics

Blood ◽

10.1182/blood-2009-07-230821 ◽

2010 ◽

Vol 115 (6) ◽

pp. 1137-1144 ◽

Cited By ~ 35

Author(s):

Namita Saran ◽

Marcin Łyszkiewicz ◽

Jens Pommerencke ◽

Katrin Witzlau ◽

Ramin Vakilzadeh ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

Cell Fate ◽

T Cell Development ◽

Cell Development ◽

Cell Precursor ◽

Lineage Differentiation ◽

Multipotent Cells ◽

Kinetics Of

Abstract T-cell development in the thymus depends on continuous supply of T-cell progenitors from bone marrow (BM). Several extrathymic candidate progenitors have been described that range from multipotent cells to lymphoid cell committed progenitors and even largely T-lineage committed precursors. However, the nature of precursors seeding the thymus under physiologic conditions has remained largely elusive and it is not known whether there is only one physiologic T-cell precursor population or many. Here, we used a competitive in vivo assay based on depletion rather than enrichment of classes of BM-derived precursor populations, thereby only minimally altering physiologic precursor ratios to assess the contribution of various extrathymic precursors to T-lineage differentiation. We found that under these conditions multiple precursors, belonging to both multipotent progenitor (MPP) and common lymphoid progenitor (CLP) subsets have robust T-lineage potential. However, differentiation kinetics of different precursors varied considerably, which might ensure continuous thymic output despite gated importation of extrathymic precursors. In conclusion, our data suggest that the thymus functions to impose T-cell fate on any precursor capable of filling the limited number of progenitor niches.

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Graft-host tolerance in bone marrow transplant chimeras. Absence of graft-versus-host disease is associated with unresponsiveness to minor histocompatibility antigens expressed by all tissues

Blood ◽

10.1182/blood.v84.9.3221.bloodjournal8493221 ◽

1994 ◽

Vol 84 (9) ◽

pp. 3221-3228

Author(s):

S Brochu ◽

C Baron ◽

R Belanger ◽

C Perreault

Keyword(s):

Bone Marrow ◽

T Cell ◽

T Lymphocytes ◽

Marrow Transplant ◽

Lymphoid Cells ◽

Histocompatibility Antigens ◽

Minor Histocompatibility Antigens ◽

Cd8 Cells ◽

B10 Cells

Because bone marrow (BM) transplantation is used with increasing frequency, it is important to elucidate the mechanisms involved in the establishment of tolerance to host minor histocompatibility antigens (MiHA) in recipients transplanted with T-cell-undepleted marrow grafts. We have previously shown that BM chimeras transplanted across MiHA barriers showed specific unresponsiveness to MiHA expressed on recipient-type concanavalin A blasts. Because expression of many MiHA is tissue-specific, we wanted to determine if chimera T lymphocytes would be tolerant to MiHA expressed by all host tissues and organs. To investigate this issue, we measured in vivo proliferation of lymphoid cells from normal C57BL/10 (B10) mice and (B10-->LP) chimeras in tissues and organs of lethally irradiated syngeneic and allogeneic recipients. Donor B10 cells were either untreated, or depleted with anti-Thy-1.2, anti-CD4, or anti-CD8 antibodies. Transplantation of B10 cells in LP recipients triggered an important T-cell-dependent 125I- dUrd uptake in several organs that involved both CD4+ and CD8+ cells. Using Thy-1-congeneic mice we showed that in long-term chimeras practically all CD4+ and CD8+ T lymphocytes were derived from hematopoietic progenitors and not from mature T cells present in the BM graft. When (B10-->LP) BM chimera cells were injected to secondary recipients, no proliferation was observed in any organ of LP hosts whereas normal proliferation was seen in H-2k allogeneic hosts. Thus, in these BM chimeras, tolerance encompasses MiHA expressed by all organs.

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