Stepwise Development of Committed Progenitors in the Bone Marrow That Generate Functional T Cells in the Absence of the Thymus.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3300-3300
Author(s):  
Sussan Dejbakhsh-Jones ◽  
Marcos E. Garcia-Ojeda ◽  
Devavanii Chatterjea ◽  
Aditi Mukhopadhyay ◽  
Irving L. Weissman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Lineage ◽  
Murine Cytomegalovirus ◽  
Lymphoid Tissues ◽  
Mouse Bone Marrow ◽  
Generate Functional ◽  
T Cell Progenitors

Abstract We identified committed T cell progenitors (CTPs) in the mouse bone marrow that have not rearranged the TCR β gene, express a variety of genes associated with commitment to the T cell lineage including GATA-3 and TCF-1, Cβand Id2, and show a surface marker pattern (CD44+CD25-CD24+CD5-) that is similar to the earliest T cell progenitors in the thymus. More mature committed intermediate progenitors (CIPs) in the marrow have rearranged the TCR gene loci, express Vαand Vβgenes as well as CD3ε, but do not express surface TCR or CD3 receptors. CTPs, but not progenitors from the thymus, reconstituted the αβ T cells in the lymphoid tissues of athymic nu/nu mice. These reconstituted T cells vigorously secreted IFN- γ after stimulation in vitro, and protected the mice against lethal infection with murine cytomegalovirus (MCMV). Also CTPs from the parent strain can reconstitute an F1 MHC haplotype mismatched host. In conclusion, CTPs in wild-type bone marrow can generate functional T cells via an extrathymic pathway.

Secondary Lymphoid Tissues Are Not Required for the Induction of GVHD Following Allogeneic BMT: A Shifting Paradigm for T Cell Allo-Activation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3170-3170
Author(s):  
Ines A. Silva ◽  
Krystyna Olkiewicz ◽  
Jacquelyn M. Fisher ◽  
Meghana N. Chaudhary ◽  
Kevin Vannella Vannella ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Major Complication ◽  
Scoring Systems ◽  
Lymphoid Tissues ◽  
Target Tissue

Abstract Allogeneic (allo) bone marrow transplantation (BMT) is the only curative option for many patients with malignant and non-malignant diseases. Acute graft versus host disease (GVHD) is the major complication of allo-BMT and limits the utility of this treatment strategy. The induction of GVHD fundamentally depends upon the activation of donor T cells by host antigen presenting cells (APCs), and the prevailing hypothesis is that these critical interactions occur in secondary lymphoid organs, such as lymph nodes (LN) Peyer’s patches (PP), and spleen (SP). We tested this hypothesis by using a well established, MHC disparate, murine SCT system (Balb/c → B6) and homozygous aly/aly (alymphoplasia) mice that are deficient in all LN and PP and heterozygous aly/+ littermate controls. Lethally irradiated, splenectomized, aly/aly mice (LN/PP/SP −/ −) and aly/+ sham mice (LN/PP/SP +/+) received BMT either from syngeneic (aly/aly) or allo (Balb/c) donors. In some experiments, wild-type B6 recipients of B6 or Balb/c BMT served as additional negative and positive GVHD controls respectively. The severity of GVHD was assessed by survival and well-described scoring systems of both clinical and target organ disease. As expected, greater than 95% of syngeneic (syn) BMT recipients survived and were indistinguishable from naïve, un-transplanted controls, whereas LN/PP/SP +/+ mice receiving allo-BMT showed significant signs of GVHD with ~40% mortality by day 49. All LN/PP/SP −/ − allo-BMT recipients also survived, but surprisingly, examination demonstrated that they too developed significant clinical GVHD compared to syn controls (score: 3.2 vs. 0.85) that was comparable in severity to LN/PP/SP +/+ mice (3.1). Moreover, histopathologic analysis demonstrated that LN/PP/SP −/ − allo-BMT recipients developed significantly greater GVHD target tissue damage in the liver, intestinal tract and skin compared to syn controls. In fact, LN/PP/SP −/ − allo-BMT recipients developed more severe hepatic GVHD compared to allo littermate (LN/PP/SP +/+) controls (30.8±1.9 vs. 20.7±2.2; p < 0.01). Similar differences in liver GVHD was also seen between allo groups as early as day 7 (16.0±2.2 vs. 7.3±0.9; p < 0.01). We next tested the ability of host aly/aly and aly/+ APCs to stimulate donor Balb/c T cells in vitro. No differences in proliferation, IFN γ production or CTL generation were detected, thus showing that the allo-stimulatory capacity of host APCs was not different between groups. In order to ascertain what extra-lymphoid host tissues might serve as initial sites for allo-antigen exposure, we examined donor T cell expansion (CD3+), activation (CD69+) and proliferation (CFSE) in the bone marrow compartment 3 days after BMT. We found that in each case, LN/PP/SP −/ − allo-BMT recipients had significantly higher numbers / divisions compared to allo, littermate, (LN/PP/SP +/+) controls. Collectively, these data challenge the paradigm that secondary lymphoid tissues are required for GVHD induction, and suggest that the bone marrow may represent an alternative site for allo-antigen recognition and donor T cell activation.

scholarly journals T-Lymphocyte precursors. I. Synergy between precursor and mature T lymphocytes in the response to concanavalin A.

1976 ◽  
Vol 144 (2) ◽  
pp. 456-466 ◽  
Author(s):  
J J Cohen ◽  
S S Fairchild
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Concanavalin A ◽  
Bone Marrow Cells ◽  
Mouse Bone Marrow ◽  
Synergistic Activity ◽  
Preincubation Medium

When mouse bone marrow cells are mixed with cortisol-resistant thymocytes and stimulated in vitro with concanavalin A, the mitogenic response observed is much greater than additive, that is, it is synergistic. Between 94 and 96% of responding cells could be identified as T cells (Thy-1 positive) and of these, 79-100% derived from the cortisol-resistant thymocyte population, not from the bone marrow. Purified macrophages could not replace bone marrow; and marrow depleted of mature T or B cells worked as well as normal marrow. Thus, T and B cells and macrophages were ruled out as the synergizing cell of bone marrow. Nude spleen contained 10 times as many precursors of T cells as did nude marrow and was 10 times better at synergy with cortisol-resistant thymocytes. This implication of the pre-T cell as synergizer was supported by the finding that the synergistic activity of marrow was lost on preincubation, but maintained if the preincubation medium contained thymosin or cyclic AMP. Thus, the ability to enhance the response of relatively mature T cells to Con A is a property of pre-T cells. It is anticipated that this property will allow more detailed studies of T-cell precursor development in mice, and possibly in man.

scholarly journals Many roads, one destination for T cell progenitors

2005 ◽  
Vol 202 (1) ◽  
pp. 11-13 ◽  
Author(s):  
Howard T. Petrie ◽  
Paul W. Kincade
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Lineage ◽  
Experimental Approaches ◽  
T Cell Progenitors

The thymus manufactures new T cells throughout life but contains no self-renewing potential. Instead, replenishment depends on recruitment of bone marrow–derived progenitors that circulate in the blood. Attempts to identify thymic-homing progenitors, and to assess the degree to which they are precommitted to the T cell lineage, have led to complex and sometimes conflicting results. As described here, this probably reflects the existence of multiple distinct types of T cell lineage progenitors as well as differences in individual experimental approaches.

Overexpression of hTLX3 in Association with Mutant IL7Rα Is Sufficient to Generate T-ALL In Vivo and to Transform Thymocytes in Vitro

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 21-21
Author(s):  
Gisele Olinto Libanio Rodrigues ◽  
Julie Hixon ◽  
Hila Winer ◽  
Erica Matich ◽  
Caroline Andrews ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
Lymphoblastic Leukemia ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Counts

Mutations of the IL-7Rα chain occur in approximately 10% of pediatric T-cell acute lymphoblastic leukemia cases. While we have shown that mutant IL7Ra is sufficient to transform an immortalized thymocyte cell line, mutation of IL7Ra alone was insufficient to cause transformation of primary T cells, suggesting that additional genetic lesions may be present contributing to initiate leukemia. Studies addressing the combinations of mutant IL7Ra plus TLX3 overexpression indicates in vitro growth advantage, suggesting this gene as potential collaborative candidate. Furthermore, patients with mutated IL7R were more likely to have TLX3 or HOXA subgroup leukemia. We sought to determine whether combination of mutant hIL7Ra plus TLX3 overexpression is sufficient to generate T-cell leukemia in vivo. Double negative thymocytes were isolated from C57BL/6J mice and transduced with retroviral vectors containing mutant hIL7R plus hTLX3, or the genes alone. The combination mutant hIL7R wild type and hTLX3 was also tested. Transduced thymocytes were cultured on the OP9-DL4 bone marrow stromal cell line for 5-13 days and accessed for expression of transduced constructs and then injected into sublethally irradiated Rag-/- mice. Mice were euthanized at onset of clinical signs, and cells were immunophenotyped by flow cytometry. Thymocytes transduced with muthIL-7R-hTLX3 transformed to cytokine-independent growth and expanded over 30 days in the absence of all cytokines. Mice injected with muthIL7R-hTLX3 cells, but not the controls (wthIL7R-hTLX3or mutIL7R alone) developed leukemia approximately 3 weeks post injection, characterized by GFP expressing T-cells in blood, spleen, liver, lymph nodes and bone marrow. Furthermore, leukemic mice had increased white blood cell counts and presented with splenomegaly. Phenotypic analysis revealed a higher CD4-CD8- T cell population in the blood, bone marrow, liver and spleen compared in the mutant hIL7R + hTLX3 mice compared with mice injected with mutant IL7R alone indicating that the resulting leukemia from the combination mutant hIL7R plus hTLX3 shows early arrest in T-cell development. Taken together, these data show that oncogenic IL7R activation is sufficient for cooperation with hTLX3 in ex vivo thymocyte cell transformation, and that cells expressing the combination muthIL7R-hTLX3 is sufficient to trigger T-cell leukemia in vivo. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals T-cell regeneration after bone marrow transplantation: differential CD45 isoform expression on thymic-derived versus thymic-independent progeny

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2585-2594 ◽  
Author(s):  
CL Mackall ◽  
L Granger ◽  
MA Sheard ◽  
R Cepeda ◽  
RE Gress
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Cell Receptor ◽  
Cell Regeneration ◽  
Thymic Function ◽  
T Cell Progenitors ◽  
Isoform Expression

Abstract To study the source of regenerated T cells after bone marrow transplantation (BMT), lethally irradiated thymectomized and thymus- bearing C57BL/6 (Thy 1.2+) mice were injected with syngeneic T-cell depleted bone marrow (TCD BM) cells and graded numbers of congenic B6/Thy 1.1+ lymph node (LN) cells. LN cell expansion was the predominant source for T-cell regeneration in thymectomized hosts but was minimal in thymus-bearing hosts. Analysis of T-cell receptor (TCR) expression on LN progeny showed a diverse V beta repertoire. Therefore, peripheral T-cell progenitors exist within V beta families, but expansion of these progenitors after BMT is downregulated in the presence of a functional thymus. CD4+ cells derived from BM versus LN in thymus-bearing hosts displayed differential CD44 and CD45 isoform expression. BM-derived cells were primarily CD45RB+CD44lo and LN derived cells were nearly exclusively CD45RB- CD44hi. In thymectomized hosts, BM, host, and LN CD4+ progeny were CD45RB- CD44hi. We conclude that T-cell regeneration via peripheral T-cell progenitors predominates in hosts lacking thymic function and gives rise to T cells that display a “memory” phenotype. In contrast, the ability to generate sizable populations of “naive” type T cells after BMT appears limited to the prethymic progenitor pool and could serve as a marker for thymic regenerative capacity.

scholarly journals Existence of a pool of T-lymphocyte colony-forming cells (T-CFC) in human bone marrow and their place in the differentiation of the T- lymphocyte lineage

Blood ◽  
1981 ◽  
Vol 58 (5) ◽  
pp. 911-915 ◽  
Author(s):  
F Triebel ◽  
WA Robinson ◽  
AR Hayward ◽  
PG Goube de Laforest
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
T Lymphocyte ◽  
Cell Lineage ◽  
Marrow Graft ◽  
In Vitro Proliferation ◽  
Complement Dependent Cytotoxicity ◽  
Self Tolerance ◽  
Proliferation And Differentiation

Abstract The existence and characteristics of bone marrow T-cell progenitors have not yet been established in man. Several pieces of evidence such as the reconstitution of certain immunodeficiencies by bone marrow graft suggest that T-cell precursors are present in the bone marrow. We report the growth of T-cell colonies from bone marrow populations using PHA-stimulated lymphocyte-conditioned medium containing T-cell growth factor (TCGF). Rosetting experiments and complement-dependent cytotoxicity assays with monoclonal antibodies indicate that the bone marrow T colony-forming cells (T-CFC) are E- OKT 3- and la+, i.e., immature progenitors. The colonies derived from these cells have the phenotype of mature T cells: E + OKT 3 + la- with either helper (OKT 4+) and suppressor (OKT 8 +) antigens. These results suggest that a thymic microenvironment may not be necessary for the in vitro proliferation and differentiation of the T-cell lineage in adult humans. These methodologies may permit direct investigation of early phenomena concerning the T-cell lineage, such as the acquisition of self-tolerance, the formation of a repertoire of specificities, and the HLA restriction phenomena that we believe takes place before the thymic maturation.

scholarly journals TRANCE (Tumor Necrosis Factor [TNF]-related Activation-induced Cytokine), a New TNF Family Member Predominantly Expressed in T cells, Is a Dendritic Cell–specific Survival Factor

1997 ◽  
Vol 186 (12) ◽  
pp. 2075-2080 ◽  
Author(s):  
Brian R. Wong ◽  
Régis Josien ◽  
Soo Young Lee ◽  
Birthe Sauter ◽  
Hong-Li Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Dominant Negative ◽  
Mouse Bone Marrow ◽  
Survival Factor ◽  
Necrosis Factor

TRANCE (tumor necrosis factor [TNF]–related activation-induced cytokine) is a new member of the TNF family that is induced upon T cell receptor engagement and activates c-Jun N-terminal kinase (JNK) after interaction with its putative receptor (TRANCE-R). In addition, TRANCE expression is restricted to lymphoid organs and T cells. Here, we show that high levels of TRANCE-R are detected on mature dendritic cells (DCs) but not on freshly isolated B cells, T cells, or macrophages. Signaling by TRANCE-R appears to be dependent on TNF receptor–associated factor 2 (TRAF2), since JNK induction is impaired in cells from transgenic mice overexpressing a dominant negative TRAF2 protein. TRANCE inhibits apoptosis of mouse bone marrow–derived DCs and human monocyte-derived DCs in vitro. The resulting increase in DC survival is accompanied by a proportional increase in DC-mediated T cell proliferation in a mixed leukocyte reaction. TRANCE upregulates Bcl-xL expression, suggesting a potential mechanism for enhanced DC survival. TRANCE does not induce the proliferation of or increase the survival of T or B cells. Therefore, TRANCE is a new DC-restricted survival factor that mediates T cell–DC communication and may provide a tool to selectively enhance DC activity.

scholarly journals Cells in bone marrow and in T cell colonies grown from bone marrow can suppress generation of cytotoxic T lymphocytes directed against their self antigens.

1980 ◽  
Vol 152 (1) ◽  
pp. 54-71 ◽  
Author(s):  
S Muraoka ◽  
R G Miller
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
T Lymphocytes ◽  
Cytotoxic Activity ◽  
Cytotoxic T Lymphocytes ◽  
Suppressor Cells ◽  
Mouse Bone Marrow ◽  
Cytotoxic Lymphocyte ◽  
Radiation Resistant

Both normal mouse bone marrow and cells from T cell-containing colonies grown in vitro from normal bone marrow contain cells which can specifically suppress the development of cytotoxic T lymphocytes capable of recognizing alloantigens on the bone marrow or colony cells. Suppression, as assessed by reduction in cytotoxic activity, is produced by adding bone marrow or colony cells to mixed lymphocyte reactions between lymph node responder cells and irradiated histoincompatible spleen stimulator cells. The cytotoxic activity is reduced if the added bone marrow or colony cells are syngeneic or semisyngeneic to the stimulator cells but not if they are allogeneic. Suppression results from a reduction in the number of cytotoxic lymphocyte precursor cells activated in the cultures. The suppressor cells in bone marrow are radiation sensitive and Thy-1 negative; those in colonies grown from bone marrow are radiation resistant and Thy-1 positive.

Immunosupressive Property of Mesenchymal Stem Cells (MSCs) in Mixed Lymphocyte Reactions In Vitro.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4313-4313 ◽  
Author(s):  
Jianyong Li ◽  
Lijuan Meng ◽  
Yu Zhu ◽  
Hua Lu ◽  
Changgeng Ruan
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
T Cell Subsets ◽  
Bone Marrow Mscs ◽  
Human Bone Marrow Mscs ◽  
Mixed Lymphocyte Reactions ◽  
Activation Phase

Abstract Meesnchymal stem cells (MSCs) were successfully used in the prevention and treatment of graft versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. To further explore the immunosuppressive property of human bone marrow (MSCs) in alloantigen-induced mixed lymphocyte reactions (MLRs) in vitro, human bone marrow MSCs and lymphocytes were prepared from healthy volunteers. MSCs were expanded in vitro in Mesencult serum free media. MSCs were cocultured with one-way MLRs and bidirectional MLRs, responder cells were labeled with carboxyfluorescein diacetate- succinimidyl ester (CFSE) in bidirectional MLRs. Cell Counting Kit-8(CCK-8)kit was used in cell proliferation detection, T-cell subsets were analyzed by flow cytometry (FCM). The results showed that MSCs were positive for CD105, CD73, CD13, CD90 and were negative for hematopoietic cell markers. In one-way MLRs, MSCs down-regulated alloantigen-induced lymphocyte expansion in a dose-dependent and MHC-independend manner. In two-way MLRs, MSCs suppressed proliferation of CFSE positive cells. T cell subsets were changed: Th2 and Tc2 were down-regulated. Th2 was reduced from 1.70% to 0.65%, and Tc2 reduced from 1.10% to 0.47%, while Th1 and Tc1 were unaffected. T cells that became CD69+, which was an early activation marker, were significantly up-regulated from 7.14% to 26.12% and CD4+CD25+T regulatory cells (CD4+CD25+Tr) were up-regulated from 4.04% to 6.19%, which indicating that suppression did not interfere with activation phase of T cells and might be mediated by CD4+CD25+Tr partly. We conclede that MSCs down-regulated alloantigen-induced lymphocyte expansion. The immunosupressive effect might involve in post-activation phase of T cells. CD4+CD25+Tr might contribute to the suppressory activity of MSCs.

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