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 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

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 Irradiation-Mediated Rescue of T Cell–Specific V(D)j Recombination and Thymocyte Differentiation in Severe Combined Immunodeficient Mice by Bone Marrow Cells

1999 ◽  
Vol 190 (9) ◽  
pp. 1257-1262 ◽  
Author(s):  
Chiyu Wang ◽  
Molly A. Bogue ◽  
Jonathan M. Levitt ◽  
David B. Roth
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
T Cell Receptor ◽  
T Lymphocyte ◽  
Bone Marrow Cells ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Immunodeficient Mice ◽  
Thymocyte Differentiation ◽  
Marrow Cells

In SCID (severe combined immunodeficient) mice, proper assembly of immunoglobulin and T cell receptor (TCR) genes is blocked by defective V(D)J recombination so that B and T lymphocyte differentiation is arrested at an early precursor stage. Treating the mice with gamma irradiation rescues V(D)J rearrangement at multiple TCR loci, promotes limited thymocyte differentiation, and induces thymic lymphomas. These effects are not observed in the B cell lineage. Current models postulate that irradiation affects intrathymic T cell precursors. Surprisingly, we found that transfer of irradiated SCID bone marrow cells to unirradiated host animals rescues both TCR rearrangements and thymocyte differentiation. These data indicate that irradiation affects precursor cells at an earlier stage of differentiation than was previously thought and suggest new models for the mechanism of irradiation rescue.

scholarly journals Generation of leukemia-reactive cytotoxic T lymphocyte clones from the HLA-identical bone marrow donor of a patient with leukemia.

1992 ◽  
Vol 176 (5) ◽  
pp. 1283-1289 ◽  
Author(s):  
L M Faber ◽  
S A van Luxemburg-Heijs ◽  
R Willemze ◽  
J H Falkenburg
Keyword(s):  
Bone Marrow ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Allogeneic Bone Marrow Transplantation ◽  
Hla Class I ◽  
Leukemic Cells ◽  
Allogeneic Bone ◽  
Marrow Graft ◽  
Specific Lysis

Allogeneic bone marrow transplantation (BMT) has been associated with a graft-vs.-leukemia (GVL) reactivity. Since T cell depletion of the bone marrow graft has decreased the risk of graft-vs.-host disease (GVHD), but has been associated with higher rates of leukemia relapse, GVL reactivity is probably caused by donor-derived T lymphocytes. Previously, we demonstrated that minor histocompatibility (mH) antigen-specific cytotoxic T lymphocyte (CTL) clones, generated from patients after BMT, are capable of major histocompatibility complex-(MHC) restricted lysis of (clonogenic) myeloid leukemic cells. Here, we investigated whether donor-derived leukemia-specific CTL clones can be generated in vitro, before BMT, using irradiated leukemic cells from a patient with acute myeloid leukemia as stimulator cells, and peripheral blood or bone marrow from the HLA genotypically identical sibling donor as responder cells. Several CTL lines were generated that showed specific lysis (> 50%) of the recipient leukemic cells in a 51Cr-release assay. Two of these CTL lines were cloned by limiting dilution in the presence of the irradiated recipient cells. Multiple leukemia-reactive, HLA class I and II-restricted clones with various specificities could be established. These alloreactive, antileukemic CTL clones may cause GVL reactivity after BMT, and may be used as adjuvant immunotherapy in the treatment of leukemia.

scholarly journals Dendritic Cell Cross Presentation of RBC Antigens in-Vivo Is Not Affected By RBC Storage Duration and Requires Red Pulp Macrophage "Help" in-Vitro

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3845-3845
Author(s):  
Amy Tang ◽  
Abdelhadi Rebbaa ◽  
Steven L Spitalnik ◽  
Eldad A. Hod ◽  
Stuart Phillip Weisberg
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Refrigerated Storage ◽  
Marrow Graft ◽  
Cross Presentation ◽  
Fresh Rbcs ◽  
Red Pulp

Abstract BACKGROUND: Chronic transfusion is associated with an increased risk of bone marrow graft rejection. In prior studies with mouse models, minor histocompatibility antigens in red blood cell (RBC) and platelet products were presented in the context of recipient MHC class I to prime recipient cytotoxic T cells; these represent cross presentation and cross priming, respectively. Once primed in the recipient, these T cells may attack allogeneic bone marrow grafts. Thus, understanding the mechanism of transfusion-induced T cell cross priming may lead to new methods to reduce bone marrow graft rejection in chronically transfused patients. Cross presentation is performed by a specialized subset of antigen presenting cells (APCs) - CD11b lo, XCR1+ dendritic cells (XCR DCs). Transfusion of RBCs after prolonged refrigerated storage induces erythrophagocytosis and pro-inflammatory gene expression in the spleen. Fluorescent tracking of transfused RBCs showed that splenic red pulp macrophages (RPMs) ingest the majority of damaged RBCs, but RPMs are weak APCs. Splenic dendritic cells, including XCR DCs, also display increased uptake of stored vs. fresh RBCs. These data suggested that refrigerated storage may increase cross presentation of RBC antigens, thereby enhancing T cell cross priming. AIMS: To compare T cell cross priming after transfusion of fresh and refrigerator-stored RBCs, a mouse model was used with transgenic OVA-carrying RBCs as the antigen source and transgenic naive MHC class I-restricted (H-2Kb) OVA-specific T cells (OT-1) as responders. In parallel, an in-vitro system was established to determine the cellular elements required for cross presentation of RBC antigens. METHODS: Purified CD8 T cells from OT-1 mice were loaded with the cell proliferation tracking dye Cell Trace Far Red (CTFR) and adoptively transferred (4 x 10e6 per mouse) into cohorts of 8-12 week old C57BL/6 GFP+ mice (n=3 per group). The next day mice were transfused with 400 uL of fresh (<24 hours old), or stored RBCs (14 days old) from transgenic HOD mice (RBCs express surface HEL, OVA, and Duffy antigens). After 96 hours, flow cytometry was used to assess OT-1 cell proliferation by dye dilution and the expression of activation markers CD44, CD122 and CD62L. Control transfusions with non-HOD GFP+ RBCs confirmed the antigen specificity of the response, and transfusions of HOD blood that had undergone RBC lysis ruled out direct antigen presentation by MHC identical white cells in the transfusate. For the in-vitro cross presentation assay, 1x10e5 CTFR-loaded OT-1 cells were plated in U-bottom 96 well plates with all possible combinations of fresh or stored HOD RBCs (50 x 10e6 per well), bone marrow Flt3L-derived C57BL/6 murine dendritic cells (Flt3L-DCs, 5 X 10e4 per well), and magnetically selected BALB/c (H-2Kd) RPMs (5 x 10e4 per well). MHC mismatch rules out antigen presentation by BALB/c RPMs (H-2Kd) to OT-I T cells (H-2Kb). RESULTS: Transfusion of both fresh and stored HOD RBCs induced vigorous proliferation and activation of OT-1 cells. After 4 days, no differences were seen in the proliferation and activation profiles of OT-1 cells in mice receiving fresh (78±4% CD44hi, CTFR diluted) vs. stored (79±5%) HOD RBCs. The in-vitro cross presentation assay showed weak to absent OVA-specific OT-1 proliferation with co-cultures including fresh or stored HOD RBCs alone, and fresh or stored HOD RBCs plus Flt3L-DCs. In contrast, cultures including RPMs and Flt3L-DCs showed enhanced OVA-specific OT-1 proliferation with fresh (29±10% CTFR diluted) and stored (25±2%) HOD RBCs. CONCLUSION: Cross priming by fresh RBCs was stronger than expected based on prior studies showing minimal RBC uptake by XCR DCs after fresh GFP + RBC transfusion. Cross priming in this system may be more sensitive due to the high frequency of antigen specific T cells and, thus, is saturated by the small antigen load delivered by fresh transfusion. It is also possible that direct uptake of RBCs by DCs harms the cross-presentation machinery and offsets the effect of increased RBC antigen delivery. Optimal cross-presentation of RBC antigen may require cooperation with cells functionally specialized for metabolizing RBC by-products. Indeed, the in-vitro study shows RPMs promote DC-mediated cross presentation of antigens on fresh and stored RBCs. Thus, RPMs may share ingested RBC antigen with adjacent DCs and increase DC activation by secreting inflammatory cytokines. . Figure Figure. Disclosures No relevant conflicts of interest to declare.

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.

scholarly journals Isolation of an early T-cell precursor (CFU-TL) from human bone marrow

Blood ◽  
1990 ◽  
Vol 75 (5) ◽  
pp. 1064-1068 ◽  
Author(s):  
JM Bertho ◽  
MD Mossalayi ◽  
AH Dalloul ◽  
G Mouterde ◽  
P Debre
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
High Capacity ◽  
Cell Lineage ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Differentiation Potential ◽  
T Cell Clones ◽  
Cell Clones

Abstract CD2-CD3-CD4-CD8- human bone marrow (BM) cells were previously shown to generate T-cell clones in vitro. This capacity was abolished after treatment of this population with anti-CD7 monoclonal antibody and complement. In this study, using rosetting with sheep erythrocytes, complement-dependent cytotoxicity, and specific immunoadherence method, we isolated a minor BM subset that contained more than 80% CD7+CD2-CD3- CD4-CD8- cells with small lymphoid cell morphology. They comprised most early T-cell precursors (CFU-TL) as they displayed high capacity to generate T-cell clones when cultured in limiting dilutions. CFU-TL nature of these cells was also confirmed by the sequential expression of mature T-cell specific markers on their surface after in vitro induction. This BM subset also contained 2% to 3% CFU-GM precursors. Together, these results pointed to the existence of BM CD7+CD2- precursors with high differentiation potential and showed the commitment of most of them to T-cell lineage.

scholarly journals Abnormal in vitro proliferation and differentiation of T cell colony-forming cells in patients with tropical spastic paraparesis/human T lymphocyte virus type I (HTLV-I)-associated myeloencephalopathy and healthy HTLV-I carriers.

1993 ◽  
Vol 177 (3) ◽  
pp. 741-750 ◽  
Author(s):  
Y Lunardi-Iskandar ◽  
A Gessain ◽  
V H Lam ◽  
R C Gallo
Keyword(s):  
Growth Factors ◽  
T Cell ◽  
Virus Type ◽  
T Lymphocyte ◽  
Spastic Paraparesis ◽  
Type I ◽  
Proliferation And Differentiation ◽  
Human T Lymphocyte ◽  
Cell Colony

T cell colonies were generated from the peripheral blood mononuclear cells (PBMC) of 10 patients with tropical spastic paraparesis/human T lymphocyte virus type I (HTLV-I)-associated myeloencephalopathy (TSP/HAM), two healthy HTLV-I carriers, and 17 healthy HTLV-I-seronegative subjects. PBMC were cultured in methylcellulose in the absence of added growth factors (spontaneous T cell colonies), or in the presence of phorbol myristate acetate and interleukin 2 (induced T cell colonies). PBMC T cell colony-forming cells (T-CFC) from all TSP/HAM patients and HTLV-I carriers were able to grow in the absence of added growth factors and/or mitogenic stimulation. Pooled spontaneous and induced colonies were composed of cells bearing CD3+, CD4+, CD8+, and CD1+ antigens. Colonies from normal HTLV-I-seronegative subjects displayed mature cells bearing the CD3+, CD4+, CD8+, and CD1- surface phenotype. In addition, spontaneous and induced T cell colonies expressed HTLV-I antigens in 18-38% of the cells from TSP/HAM patients and HTLV-I carriers. These results demonstrate that HTLV-I infection is associated with an abnormal proliferation and differentiation of T cell progenitors in vitro and that the T-CFC from HTLV-I-seropositive individuals are infected, suggesting that T-CFC abnormalities may play a predominant role in the pathophysiology of HTLV-I.

scholarly journals Immunologic Self-Tolerance Maintained by Cd25+Cd4+Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–Associated Antigen 4

2000 ◽  
Vol 192 (2) ◽  
pp. 303-310 ◽  
Author(s):  
Takeshi Takahashi ◽  
Tomoyuki Tagami ◽  
Sayuri Yamazaki ◽  
Toshimitsu Uede ◽  
Jun Shimizu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Lymphocyte ◽  
Cd4 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Costimulatory Molecule ◽  
Self Tolerance

This report shows that cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) plays a key role in T cell–mediated dominant immunologic self-tolerance. In vivo blockade of CTLA-4 for a limited period in normal mice leads to spontaneous development of chronic organ-specific autoimmune diseases, which are immunopathologically similar to human counterparts. In normal naive mice, CTLA-4 is constitutively expressed on CD25+CD4+ T cells, which constitute 5–10% of peripheral CD4+ T cells. When the CD25+CD4+ T cells are stimulated via the T cell receptor in vitro, they potently suppress antigen-specific and polyclonal activation and proliferation of other T cells, including CTLA-4–deficient T cells, and blockade of CTLA-4 abrogates the suppression. CD28-deficient CD25+CD4+ T cells can also suppress normal T cells, indicating that CD28 is dispensable for activation of the regulatory T cells. Thus, the CD25+CD4+ regulatory T cell population engaged in dominant self-tolerance may require CTLA-4 but not CD28 as a costimulatory molecule for its functional activation. Furthermore, interference with this role of CTLA-4 suffices to elicit autoimmune disease in otherwise normal animals, presumably through affecting CD25+CD4+ T cell–mediated control of self-reactive T cells. This unique function of CTLA-4 could be exploited to potentiate T cell–mediated immunoregulation, and thereby to induce immunologic tolerance or to control autoimmunity.

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