Thymus-autonomous T cell development in the absence of progenitor import

Thymus function is thought to depend on a steady supply of T cell progenitors from the bone marrow. The notion that the thymus lacks progenitors with self-renewal capacity is based on thymus transplantation experiments in which host-derived thymocytes replaced thymus-resident cells within 4 wk. Thymus grafting into T cell–deficient mice resulted in a wave of T cell export from the thymus, followed by colonization of the thymus by host-derived progenitors, and cessation of T cell development. Compound Rag2−/−γc−/−KitW/Wv mutants lack competitive hematopoietic stem cells (HSCs) and are devoid of T cell progenitors. In this study, using this strain as recipients for wild-type thymus grafts, we noticed thymus-autonomous T cell development lasting several months. However, we found no evidence for export of donor HSCs from thymus to bone marrow. A diverse T cell antigen receptor repertoire in progenitor-deprived thymus grafts implied that many thymocytes were capable of self-renewal. Although the process was most efficient in Rag2−/−γc−/−KitW/Wv hosts, γc-mediated signals alone played a key role in the competition between thymus-resident and bone marrow–derived progenitors. Hence, the turnover of each generation of thymocytes is not only based on short life span but is also driven via expulsion of resident thymocytes by fresh progenitors entering the thymus.

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LRF Is Indispensable for Hematopoietic Stem Cell Function Via Blocking Notch1-Mediated T Cell-Instructive Signals in the Bone Marrow Niche.

Blood ◽

10.1182/blood.v114.22.81.81 ◽

2009 ◽

Vol 114 (22) ◽

pp. 81-81 ◽

Cited By ~ 1

Author(s):

Sung-UK Lee ◽

Manami Maeda ◽

Nagisa Sakurai ◽

Freddy Radtke ◽

Takahiro Maeda

Keyword(s):

Bone Marrow ◽

T Cell ◽

B Cell ◽

Target Gene ◽

T Cell Development ◽

Cell Development ◽

B Cell Development ◽

Self Renewal ◽

Hematopoietic Stem ◽

Hematopoietic System

Abstract Abstract 81 Hematopoietic stem cells (HSC) have the ability to self-renew and give rise to all hematopoietic lineage cells. Understanding signals that regulate the balance between self-renewal and differentiation of HSCs is an important issue in stem cell biology as well as regenerative medicine. Notch signals are critical regulators of the lymphoid lineage fate, but their role in adult HSC function is currently under debate. We explored the role of the LRF (Leukemia/Lymphoma Related Factor), a Notch repressor (also known as Zbtb7a, pokemon, OCZF and FBI-1) in HSC function, as it plays key roles in embryonic development, oncogenesis, and hematopoiesis. Conditional inactivation of the LRF gene in mouse HSCs (LRFF/FMx1-Cre mice) led to the development of CD4/CD8 DP (double positive) T-cells at the expense of B-cell development in the bone marrow (BM) in a Notch-dependent manner. Absolute numbers of the most primitive HSCs (LT-HSCs), defined as CD150+CD48−Flt3−Vcam-1+IL7Rα−LSK (Lin−Sca1+c-Kit+), were significantly reduced, while lymphoid-biased multi-potential progenitors (LMPPs: CD150−CD48+Flt3+Vcam-1+/−IL7Rα−LSK) and common lymphoid progenitors (CLPs: Lin−CD150−CD48+Flt3+Vcam-1−IL7Rα+) were barely detectable in LRFF/FMx1-Cre mice one month after pIpC injection. Enhanced T cell development and concomitant loss of B cell development was also seen in LRF−/− fetal liver (FL). Lin−IL7Rα+c-Kit+PIR+ (Paired Immunoglobulin-like receptors) T cell precursors were significantly increased in LRF−/− FL, indicating that Notch-mediated aberrant lymphoid fate determination also takes place during fetal hematopoiesis. To address which Notch gene(s) are targeted by LRF, we studied the HSC/progenitor population of conditional LRF knockout (LRFF/FMx1-Cre) as well as LRF/Notch1 double conditional knockout mice (LRFF/FNotch1F/FMx1-Cre). In the absence of Notch1, normal B cell development was restored in LRFF/FMx1-Cre mice. Reduction of LT-HSCs in LRFF/FMx1-Cre resulted from high Notch1 activity, as loss of Notch1 rescued LT-HSC numbers, suggesting that LRF functions to maintain HSCs and normal lymphoid fate by blocking Notch1. HSCs in active cell cycle are sensitive to 5-fluoro-uracil (5-FU) treatment, which causes remaining dormant HSCs to be recruited into the cell cycle to rapidly produce new cells and to quickly re-establish the hematopoietic system. To examine the self-renewal capacity of LRF deficient LT-HSC, LRFF/FMx1-Cre mice were treated with 5-FU after pIpC injection and the recovery of LT-HSC numbers examined. While control LT-HSC numbers recovered to pretreatment levels 3 wk after 5-FU treatment, levels in LRFF/FMx1-Cre mice remained low, accompanied by DP T cell development in the BM. Furthermore, after 5-FU treatment, LT-HSC numbers of LRFF/FNotch1F/FMx1-Cre were compatible to those of control and LRFF/FMx1-Cre mice, indicating that lack of self-renewal capacity in LRF deficient LT-HSCs was due to excessive differentiation toward T cells caused by Notch1. In support of this idea, when mice were given 5-FU weekly as a challenge to assess their HSC function in vivo, the survival percentage in LRFF/FMx1-Cre mice was much lower than in controls (0% versus 50% in 1 month, P <0.0001) and that of LRFF/FNotch1F/FMx1-Cre mice was compatible to controls. Serial bone marrow transplant experiments further demonstrated functional defects of LRF deficient HSCs, as they failed to reconstitute the hematopoietic system in secondary recipients. Microarray analysis and subsequent Gene Set Enrichment Analysis demonstrated upregulation of genes that were enriched in progenitor compartments. Since LRF can act as a transcriptional repressor, mRNA levels of Notch receptors and Notch ligands were examined using the same data set. A Notch target gene Hes1, but not Notch1 itself, was upregulated, and increased levels of Hes1 was also confirmed by real-time q-PCR in FACS-sorted LT-HSCs, as well as in 10.5 d.p.c whole embryos. These data suggest that LRF does not transcriptionally regulate Notch1, as LRF loss led to Notch1 target gene activation at the LT-HSC level without affecting Notch1 mRNA. Our genetic studies clearly indicate that LRF is indispensable for the maintenance of the HSC pool by repressing T cell-instructive signals mediated by Notch1 in the BM niche. Our findings shed new light on the regulatory mechanisms underlying the balance between HSC self-renewal and differentiation. Disclosures: No relevant conflicts of interest to declare.

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Notch Repression by LRF Is Necessary for the Maintenance of Adult Hematopoietic Stem Cell Pool.

Blood ◽

10.1182/blood.v116.21.2633.2633 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2633-2633

Author(s):

Sung-UK Lee ◽

Min Li ◽

Manami Maeda ◽

Nagisa Sakurai ◽

Yuichi Ishikawa ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

T Cell ◽

T Cell Development ◽

Cell Development ◽

Self Renewal ◽

Hematopoietic Stem ◽

Deficient Mice

Abstract Abstract 2633 Among the different stem cells, hematopoietic stem cells (HSCs) are one of the best studied and characterized stem cells. To maintain life-long hematopoiesis in the bone marrow (BM), signals governing the balance between self-renewal and differentiation are tightly regulated in HSC compartment. Notch signals are critical regulators of the lymphoid lineage fate, but their role in adult HSC function in the BM is currently under debate. LRF (Leukemia/Lymphoma Related Factor, also known as Zbtb7a/pokemon) is a transcription factor that acts as a proto-oncogene and plays a key role in lymphoid and erythroid development. Previously we reported that the pool of LT-HSCs, CD150+CD48−Flt3−Vcam-1+/−IL7Rα−LSK (Lin−Sca-1+c-Kit+), was significantly reduced, while lymphoid-biased multi-potential progenitors (LMPPs: CD150−CD48+Flt3+Vcam-1+/−IL7Rα−LSK) and common lymphoid progenitors (CLPs: Lin−CD150−CD48+Flt3+Vcam-1−IL7Rα+) were barely detectable in LRF deficient mice. This was due to excessive differentiation of HSC into aberrant CD4/CD8 DP (double positive) T cell development in the BM caused by high Notch activity, implicating LRF role on HSC maintenance. Both gene expression profile (GSEA and DAVID analysis) and Q-PCR results indicated that LRF deficient LT-HSCs had loss of stem cell signature; but gain of T cell signature and up-regulated Notch-target gene, Hes-1, without affecting mRNA expression of Notch (1-4) or related (DLL1, DLL4, Jagged-1) genes. To determine LRF function in HSCs, we performed in vivo and in vitro experiments: 1) 5-FU (5-fluorouracil, the chemotherapy agent) treated LRF deficient mice were not able to compensate for their loss of LT-HSCs; 2) multi-lineage defects were shown in second recipient mice transplanted with 1 million of LRF deficient bone marrow cells in serial bone marrow transplantation assays, suggesting that LRF deficient LT-HSCs had defect in self-renewal and 3) LRF deficient FL-HSCs (CD150+CD48−LSK cells) were cultured on OP9 cells expressing delta-like ligand (DLL1, DLL4 and Jagged1), and enhanced T cell differentiation was only observed when they were co-cultured with delta-expressing OP9 cells. Among the Notch family, these phenotypes were Notch1-dependent. In fact, Notch1flox/floxLRFflox/floxMx1-Cre+ mice demonstrated normal LT-HSC numbers and restored B cell development, and prolonged survival over LRFflox/floxMx1-Cre+ mice in sequential 5-FU treatment in vivo. To explore which Notch-ligand(s) in BM niche is responsible for aberrant T-cell development in LRF deficient mice as well, we treated wild-type and LRFflox/floxMx1-Cre+ with anti-DLL4 antibody twice per week for 3 weeks. DLL4 blockage in LRF deficient mice rescued B cell development and prevented the development of aberrant DP T-cell development in LRF deficient mice. To further elucidate the relationship between LRF and Notch in adult HSC function, we analyzed Notch protein expression levels in HSCs and performed in-depth analysis of HSC/progenitor (HSC, LMPP and CLP) compartments in wild-type and LRF knockout (KO). Interestingly, Notch1 proteins were differentially expressed in LT-HSCs and ~50 % of them were positive for Notch1, while Notch2 was abundantly expressed in LT-HSCs. Notch1 expressing LT-HSCs were in more active cell-cycle (S phase) and absent in LRF conditional knockout mice. It is most likely that Notch1 expressing LT-HSCs were continually differentiating toward T cells in the absence of LRF, as CD4+CD8+ T cells were evident in the BM 10 months after pIpC injection. Taken together, our data strongly indicate that LRF is indispensable for hematopoietic homeostasis by preventing the lymphoid-primed HSCs from Notch/Delta-mediated T-instructive signal in the BM niche. Currently we're investigating the functional significances of Notch1 expressing LT-HSCs in detail. Our studies help us to better understand the underlying mechanism for HSC fate decision (self-renewal v.s. differentiation) in stem cell biology and its therapeutic approach in regenerative medicine. Disclosures: No relevant conflicts of interest to declare.

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Ammonium Ions Derived from Spontaneous Decomposition of L-Glutamine Inhibit Lymphoid Differentiation from Hematopoietic Stem/Progenitor Cells.

Blood ◽

10.1182/blood.v110.11.2244.2244 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2244-2244

Author(s):

Gerald J. Spangrude ◽

Birgitta Johnson ◽

Scott Cho ◽

Xiaosong Huang ◽

L. Jeanne Pierce

Keyword(s):

Bone Marrow ◽

T Cell ◽

B Cell ◽

Progenitor Cells ◽

Stromal Cell ◽

T Cell Development ◽

Cell Development ◽

Ammonium Ions ◽

Hematopoietic Stem ◽

Lymphocyte Differentiation

Abstract The ability to study lymphocyte differentiation in culture has been greatly advanced by the availability of the OP9 bone marrow stromal cell line, which was derived from an op/op mouse and thus lacks M-CSF. As a result, the normal default myeloid differentiation from bone marrow-derived stem and progenitor cells does not occur, and lymphocyte differentiation is favored. Introduction of the Notch ligand Delta-like 1 into OP9 cells results in promotion of T cell development and parallel suppression of B cell development. While the OP9-DL1 model of T cell development works quite well when fetal liver-derived progenitors are cultured, the success of T cell development from adult bone marrow-derived progenitors has been more difficult to reproduce. We have undertaken a systematic analysis of variables that can prevent efficient T cell development in OP9-DL1 cultures, and have found that one limiting factor that impacts the efficiency of differentiation of both T and B cell lineages is the accumulation of ammonium ions as a result of the spontaneous decomposition of l-glutamine. L-glutamine, which is present at 2 to 4 mM in standard tissue culture media, is unstable and will spontaneously degrade to form ammonium ions and pyroglutamic acid at a rate of 1%/day at 4°C and at a 10-fold higher rate at 37°C. To evaluate the effects of the two major products of l-glutamine decomposition on lymphoid differentiation, we added each product to differentiation cultures at 3 mM in the presence of a stable source of l-glutamine (l-alanyl-l-glutamine). Cultures were established in 1 ml containing 4×104 stromal cells (OP9 for B cell differentiation, OP9-DL1 for T cell differentiation), 1×103 bone marrow-derived lymphoid progenitors enriched by phenotype (c-kit+LinnegSca-1+Thy-1.1neg), and 5 ng/ml Flt3L plus 5 ng/ml IL-7. Every 3 to 4 days, cultures were harvested and passaged onto fresh stromal cell monolayers; lymphoid cells were counted and evaluated for surface antigen expression at each passage. While addition of pyroglutamic acid had no inhibitory effect on lymphocyte growth or differentiation, addition of ammonium chloride slowed growth and prevented differentiation of both T and B lymphocytes. Growth of the stromal cell monolayers was not affected by ammonium chloride at the concentrations utilized in these studies. We conclude that freshly-prepared culture medium, preferably containing a stabilized form of l-glutamine, is a critical aspect contributing to the success of lymphocyte differentiation cultures established from adult bone marrow cells. We also found that decreasing IL-7 concentrations to 1 ng/ml resulted in more rapid differentiation of T cells and a more balanced representation of CD4 and CD8 single positive cells. Our studies help define optimal conditions for differentiation of bone marrow-derived lymphoid progenitor cells into T and B lineages in vitro, and provide evidence that hematopoietic differentiation displays variable degrees of sensitivity to ammonium ions derived from decomposition of l-glutamine. These results will help define optimal conditions for expansion and differentiation of hematopoietic stem and progenitor cells in vitro.

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Gata2 +9.5 enhancer regulates adult hematopoietic stem cell self-renewal and T cell development

Blood Advances ◽

10.1182/bloodadvances.2021004311 ◽

2021 ◽

Author(s):

Xiaona You ◽

Yun Zhou ◽

Yuan-I Chang ◽

Guangyao Kong ◽

Erik A. Ranheim ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Hematopoietic Stem Cell ◽

Bone Marrow Cells ◽

Fetal Liver ◽

T Cell Development ◽

Cell Development ◽

Phenotypic Characterization ◽

Self Renewal ◽

Hematopoietic Stem

Mammalian GATA2 gene encodes a dual zinc finger transcription factor, which is essential for hematopoietic stem cell (HSC) generation in the aorta, gonad, mesonephros (AGM) region, HSC self-renewal, and specification of progenitor cell fates. Previously, we demonstrated that Gata2 expression in AGM is controlled by its intronic +9.5 enhancer. Gata2 +9.5 deficiency removes the E-box motif and the GATA site and depletes fetal liver HSCs. However, whether this enhancer has essential functions to regulate adult hematopoiesis has not been established. Here, we evaluate Gata2 +9.5 enhancer function in adult hematopoiesis. +9.5+/- bone marrow cells displayed reduced T cell reconstitution in a competitive transplant assay. Donor-derived analysis demonstrated a previously unrecognized function of the +9.5 enhancer in T cell development at the lymphoid-primed multipotent progenitor stage. Moreover, +9.5+/- adult HSCs displayed increased apoptosis and reduced long-term self-renewal capability in comparison with wild-type (WT) HSCs. These phenotypes were more moderate than those of Gata2+/- HSCs. Consistent with the phenotypic characterization, Gata2 expression in +9.5+/- LSKs was moderately higher than that in Gata2+/- LSKs, but lower than that in WT LSKs. Our data suggest that +9.5 deficiency compromises, without completely abrogating, Gata2 expression in adult HSCs.

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Baboon envelope LVs efficiently transduced human adult, fetal, and progenitor T cells and corrected SCID-X1 T-cell deficiency

Blood Advances ◽

10.1182/bloodadvances.2018027508 ◽

2019 ◽

Vol 3 (3) ◽

pp. 461-475 ◽

Cited By ~ 10

Author(s):

Ornellie Bernadin ◽

Fouzia Amirache ◽

Anais Girard-Gagnepain ◽

Ranjita Devi Moirangthem ◽

Camille Lévy ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Development ◽

Cell Development ◽

Hematopoietic Stem ◽

Naive T Cells ◽

Naïve T Cells ◽

T Cell Progenitors ◽

Development In Vitro

Abstract T cells represent a valuable tool for treating cancers and infectious and inherited diseases; however, they are mainly short-lived in vivo. T-cell therapies would strongly benefit from gene transfer into long-lived persisting naive T cells or T-cell progenitors. Here we demonstrate that baboon envelope glycoprotein pseudotyped lentiviral vectors (BaEV-LVs) far outperformed other LV pseudotypes for transduction of naive adult and fetal interleukin-7–stimulated T cells. Remarkably, BaEV-LVs efficiently transduced thymocytes and T-cell progenitors generated by culture of CD34+ cells on Delta-like ligand 4 (Dll4). Upon NOD/SCIDγC−/− engraftment, high transduction levels (80%-90%) were maintained in all T-cell subpopulations. Moreover, T-cell lineage reconstitution was accelerated in NOD/SCIDγC−/− recipients after T-cell progenitor injection compared with hematopoietic stem cell transplantation. Furthermore, γC-encoding BaEV-LVs very efficiently transduced Dll4-generated T-cell precursors from a patient with X-linked severe combined immunodeficiency (SCID-X1), which fully rescued T-cell development in vitro. These results indicate that BaEV-LVs are valuable tools for the genetic modification of naive T cells, which are important targets for gene therapy. Moreover, they allowed for the generation of gene-corrected T-cell progenitors that rescued SCID-X1 T-cell development in vitro. Ultimately, the coinjection of LV-corrected T-cell progenitors and hematopoietic stem cells might accelerate T-cell reconstitution in immunodeficient patients.

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Role of Mir-29b in T-Cell Development and in Cutaneous T-Cell Lymphoma Pathogenesis

Blood ◽

10.1182/blood-2020-142145 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-37

Author(s):

Anthony Mansour ◽

David Clever ◽

Colleen Isabelle ◽

Amy E Boles ◽

Kathleen McConnell ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Cell Lymphoma ◽

T Cell Development ◽

Surface Expression ◽

Cell Development ◽

Cutaneous T Cell Lymphoma ◽

Hematopoietic Stem

The role of microRNA (miR) is rapidly advancing with numerous functions discovered in cancer pathogenesis. We had previously shown a significant decrease in miR-29b levels in malignant cells isolated from peripheral blood of cutaneous T-cell lymphoma (CTCL) (Kohnken et al. Blood, 2018). Replenishing miR-29b levels in vitro induced apoptosis in leukemic cells suggesting its role as tumor suppressor miR in CTCL patients. In this study, we focused on the role of mir-29b on early T-cell development and homeostasis using the miR-29b-/- mouse model. Using knockout mouse model, we show that the homozygous deletion of miR-29b locus results in an overall decrease in T-cell numbers and density in primary and secondary lymphoid organs. We observed an early thymic involution in miR-29b-/- mice, with a 5-fold decrease in the total number of thymocytes and altered T-cell development. Using the surface expression of CD25 and CD44 on double-negative (DN) cells, we observed significant decrease of the absolute counts in the four early differentiation stages (DN1-4) in miR-29b-/- mice compared to age-matched wild-type (WT) mice: DN1 (miR-29b-/- vs. WT: 4.5 x 105 ± 1.04 vs. 1.12 x 105 ± 0.201, N=4 and 6 respectively, p < 0.05); DN2 (miR-29b-/- vs. WT: 0.83 x 105 ± 0.07 vs. 0.051 x 105 ± 0.021, N=4 and 6 respectively, p < 0.001); DN3 (miR-29b-/- vs. WT: 4.05 x 105 ± 0.38 vs. 0.54 x 105 ± 0.16, N=4 and 6 respectively, p < 0.001) and DN4 (miR-29b-/- vs. WT: 2.871 x 105 ± 0.578 x 105 vs. 0.569 ± 0.14, N=4 and 6 respectively, p < 0.01). Furthermore, miR-29b-/- mice show a significant increase in regulatory T cells in comparison to WT mice in the spleen (miR-29b-/- vs. WT: 18.48 ± 0.89 vs. 10.89 ± 0.41, N=4 and 6 respectively, p < 0.001) thymus (miR-29b-/- vs. WT: 5.80 ± 0.44 vs. 3.65 ± 0.004, N=4 and 6 respectively, p < 0.01) and bone marrow (miR-29b-/- vs. WT: 50.04 ± 3.14 vs. 37.52 ± 3.29, N=4 and 6 respectively, p < 0.05). Using single-cell RNA sequencing (scRNA-seq), we found a framework of putative genes in miR-29b deficient T-cells that overlap with CTCL pathogenesis: Ccr7, Cd69, Cd74, and Lef-1. Among thymic T cells, Ccr7 affects physiologic homing of T-cells to lymph nodes and facilitate nodal metastasis in CTCL patients. As T-cells progenitors originate from the bone marrow, we observed a severe impairment in the progenitor cell population in miR-29b-/- mice and over 4-fold reduction in the absolute number of Lin-Sca1+ckit+ cell (miR-29b-/- vs. WT: 28.42 x 103 ± 4.13 vs. 5.98 x 103 ± 1.01, N=4 and 3 respectively, p < 0.01). Using the surface expression of CD48 and CD150 on Lin-Sca1+ckit+, we observed a significant decrease in hematopoietic stem cells and multipotent progenitor cells in miR-29b-/- mice. Since impairment in T-cells development can be linked to hematopoietic stem cell defects, we interrogated the engraftment capacity of Lin-Sca1+ckit+ cells into committed cell lineages in vivo. To evaluate whether the defect in T-cells development is due to reduced ability of precursor cells, we performed transplantation of Lin-Sca1+ckit+ cells from the bone marrow of miR-29b and WT (CD45.1) mice in lethally irradiated WT (CD45.2) mice. Our results show a significant reduction in T-cells reconstitution in mice transplanted with miR-29b-/- Lin-Sca1+ckit+ cells versus the bone marrow counterpart. These deficits in T-cells populations were observed in peripheral blood, thymus, spleen, and bone marrow in miR-29b-/- transplanted mice. ScRNA-seq profiling of Lin- bone marrow cells show significant changes in miR-29b-/- and WT mice. Among the upregulated genes in the mir-29b-/- mice, several genes showed greater than a 10-fold increase in the thymus (Ifna2, Zmynd10, Plekha4, Etl4, and Gm38004). In conclusion, our results highlight the importance of mir-29b in early defects in T-cells development and help us understand the complex miR-29b regulated cellular transformation machinery in CTCL pathogenesis, thus paving path to develop novel therapeutic approaches targeting miR-29b in CTCL therapy. Disclosures No relevant conflicts of interest to declare.

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3040 – IN VITRO RECAPITULATION OF MURINE T CELL DEVELOPMENT FROM SINGLE HEMATOPOIETIC STEM CELLS

Experimental Hematology ◽

10.1016/j.exphem.2020.09.060 ◽

2020 ◽

Vol 88 ◽

pp. S51

Author(s):

Victoria Sun ◽

Amelie Montel-Hagen ◽

David Casero ◽

Steven Tsai ◽

Alexandre Zampieri ◽

...

Keyword(s):

Stem Cells ◽

T Cell ◽

Hematopoietic Stem Cells ◽

T Cell Development ◽

Cell Development ◽

Hematopoietic Stem

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Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration

Blood ◽

10.1182/blood-2005-07-2831 ◽

2006 ◽

Vol 107 (6) ◽

pp. 2453-2460 ◽

Cited By ~ 139

Author(s):

Önder Alpdogan ◽

Vanessa M. Hubbard ◽

Odette M. Smith ◽

Neel Patel ◽

Sydney Lu ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

Growth Factor ◽

Keratinocyte Growth Factor ◽

Critical Role ◽

T Cell Development ◽

Marrow Transplant ◽

Cell Development ◽

Allogeneic Bone ◽

Thymic Regeneration

AbstractKeratinocyte growth factor (KGF) is a member of the fibroblast growth factor family that mediates epithelial cell proliferation and differentiation in a variety of tissues, including the thymus. We studied the role of KGF in T-cell development with KGF-/- mice and demonstrated that thymic cellularity and the distribution of thymocyte subsets among KGF-/-, wildtype (WT), and KGF+/- mice were similar. However, KGF-/- mice are more vulnerable to sublethal irradiation (450 cGy), and a significant decrease was found in thymic cellularity after irradiation. Defective thymopoiesis and peripheral T-cell reconstitution were found in KGF-/- recipients of syngeneic or allogeneic bone marrow transplant, but using KGF-/- mice as a donor did not affect T-cell development after transplantation. Despite causing an early developmental block in the thymus, administration of KGF to young and old mice enhanced thymopoiesis. Exogenous KGF also accelerated thymic recovery after irradiation, cyclophosphamide, and dexamethasone treatment. Finally, we found that administering KGF before bone marrow transplantation (BMT) resulted in enhanced thymopoiesis and peripheral T-cell numbers in middle-aged recipients of an allogeneic BM transplant. We conclude that KGF plays a critical role in postnatal thymic regeneration and may be useful in treating immune deficiency conditions. (Blood. 2006;107:2453-2460)

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T-Cell Development from Hematopoietic Stem Cells

Molecular Biology of B-Cell and T-Cell Development ◽

10.1007/978-1-4757-2778-4_17 ◽

1998 ◽

pp. 305-336 ◽

Cited By ~ 3

Author(s):

Koichi Akashi ◽

Motonari Kondo ◽

Annette M. Schlageter ◽

Irving L. Weissman

Keyword(s):

Stem Cells ◽

T Cell ◽

Hematopoietic Stem Cells ◽

T Cell Development ◽

Cell Development ◽

Hematopoietic Stem

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Placing Ion Channels into a Signaling Network of T Cells: From Maturing Thymocytes to Healthy T Lymphocytes or Leukemic T Lymphoblasts

BioMed Research International ◽

10.1155/2015/750203 ◽

2015 ◽

Vol 2015 ◽

pp. 1-32 ◽

Cited By ~ 5

Author(s):

Oxana Dobrovinskaya ◽

Iván Delgado-Enciso ◽

Laura Johanna Quintero-Castro ◽

Carlos Best-Aguilera ◽

Rocío Monserrat Rojas-Sotelo ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Ion Channels ◽

Cell Cycle Progression ◽

T Cell Development ◽

Cell Development ◽

Signaling Network ◽

Self Renewal ◽

And Migration ◽

Regulation Of Cell Cycle

T leukemogenesis is a multistep process, where the genetic errors during T cell maturation cause the healthy progenitor to convert into the leukemic precursor that lost its ability to differentiate but possesses high potential for proliferation, self-renewal, and migration. A new misdirecting “leukemogenic” signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially. It appears that each of three groups may contain genes coding ion channels. In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death. In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels. We suggest that changes in regulation of various ion channels in different types of the T leukemias may provide the intracellular ion microenvironment favorable to maintain self-renewal capacity, arrest differentiation, induce proliferation, and enhance motility.

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