scholarly journals IFNγ and iNOS-Mediated Alterations in the Bone Marrow and Thymus and Its Impact on Mycobacterium avium-Induced Thymic Atrophy

2021 ◽  
Vol 12 ◽  
Author(s):  
Palmira Barreira-Silva ◽  
Rita Melo-Miranda ◽  
Claudia Nobrega ◽  
Susana Roque ◽  
Cláudia Serre-Miranda ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Differentiation ◽  
T Cell ◽  
Mycobacterium Avium ◽  
Caspase 3 ◽  
T Cell Differentiation ◽  
Thymic Atrophy ◽  
High Virulence ◽  
Thymocyte Differentiation ◽  
Active Caspase

Disseminated infection with the high virulence strain of Mycobacterium avium 25291 leads to progressive thymic atrophy. We previously showed that M. avium-induced thymic atrophy results from increased glucocorticoid levels that synergize with nitric oxide (NO) produced by interferon gamma (IFNγ) activated macrophages. Where and how these mediators act is not understood. We hypothesized that IFNγ and NO promote thymic atrophy through their effects on bone marrow (BM) T cell precursors and T cell differentiation in the thymus. We show that M. avium infection cause a reduction in the percentage and number of common lymphoid progenitors (CLP). Additionally, BM precursors from infected mice show an overall impaired ability to reconstitute thymi of RAGKO mice, in part due to IFNγ. Thymi from infected mice present an IFNγ and NO-driven inflammation. When transplanted under the kidney capsule of uninfected mice, thymi from infected mice are unable to sustain T cell differentiation. Finally, we observed increased thymocyte death via apoptosis after infection, independent of both IFNγ and iNOS; and a decrease on active caspase-3 positive thymocytes, which is not observed in the absence of iNOS expression. Together our data suggests that M. avium-induced thymic atrophy results from a combination of defects mediated by IFNγ and NO, including alterations in the BM T cell precursors, the thymic structure and the thymocyte differentiation.

scholarly journals IFNγ and iNOS-mediated alterations in the bone marrow and thymus and its impact on Mycobacterium avium-induced thymic atrophy

2021 ◽  
Author(s):  
Palmira Barreira-Silva ◽  
Rita Melo-Miranda ◽  
Claudia Nobrega ◽  
Susana Roque ◽  
Cláudia Serre-Miranda ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Differentiation ◽  
T Cell ◽  
Mycobacterium Avium ◽  
T Cell Differentiation ◽  
Cell Precursor ◽  
Thymic Atrophy ◽  
Multipotent Progenitors ◽  
High Virulence ◽  
Thymic Stroma

ABSTRACTDisseminated infection with the high virulence strain of Mycobacterium avium 25291 lead to progressive thymic atrophy. We previously uncovered that M. avium-induced thymic atrophy is due to increased levels of glucocorticoids synergizing with nitric oxide (NO) produced by interferon gamma (IFNγ) activated macrophages. Where and how these mediators are playing, was yet to be understood. We hypothesized that IFNγ and NO might be affecting bone marrow (BM) T cell precursors and/or T cell differentiation in the thymus. We show that M. avium infection causes a reduction on the percentage of lymphoid-primed multipotent progenitors (LMPP) and common lymphoid progenitors (CLP). Additionally, BM precursors from infected mice are unable to reconstitute thymi of RAGKO mice in an IFNγ-dependent way. Thymi from infected mice presents a NO-dependent inflammation. When transplanted under the kidney capsule of non-infected mice, thymic stroma from infected mice is unable to sustain T cell differentiation. Finally, we observed increased thymocyte death via apoptosis after infection, independent of both IFNγ and iNOS, and a decrease on activated caspase-3 positive thymocytes, that was not observed in the absence of iNOS expression. Together our data suggests that M. avium-induced thymic atrophy results from a combination of impairments, mediated by IFNγ and NO, affecting different steps of T cell differentiation from T cell precursor cells in the BM to the thymic stroma and thymocytes.

Arrest of In Vitro T Cell Differentiation of Normal Bone Marrow‐Derived CD34+Stem Cells with Thymic Epithelial Fragments from Children with AIDS

Stem Cells ◽  
1996 ◽  
Vol 14 (5) ◽  
pp. 533-547 ◽  
Author(s):  
Margaret E. Ruiz ◽  
John Freeman ◽  
John D. Bouhasin ◽  
Alan P. Knutsen ◽  
Mary J. C. Hendrix
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cell Differentiation ◽  
T Cell ◽  
T Cell Differentiation ◽  
Normal Bone Marrow ◽  
Normal Bone

Flow cytometric assessment of human T-cell differentiation in thymus and bone marrow

Blood ◽  
1992 ◽  
Vol 79 (3) ◽  
pp. 666-677 ◽  
Author(s):  
LW Terstappen ◽  
S Huang ◽  
LJ Picker
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Cell Differentiation ◽  
T Cell ◽  
Cell Surface ◽  
Expression Patterns ◽  
Antigen Expression ◽  
T Cell Differentiation ◽  
Multiparameter Flow Cytometry ◽  
Human T Cell

Abstract Using multidimensional flow cytometry we have defined and quantified the human T-cell differentiation pathway, focusing on those events occurring among the most immature thymocytes and putative bone marrow (BM) T-precursors. Early thymocytes were found to express the CD34 antigen and consisted of a mean 1.2% of cells within human pediatric (n = 9) and 2.0% in fetal thymi (n = 4). All CD34+ thymocytes were atypical blast by morphology, expressed intracytoplasmatic, but not cell surface, CD3, and were cell surface CD2+, CD5+, CD7+, CD38+, CD45+, CD45RA+, CD49d+, and LECAM-1(Leu8)high. CD34high thymocytes lacked surface expression of CD4 and CD8, but as CD34 expression diminished there was a coordinate increase in CD4 levels, followed by the appearance of CD8. The expression of CD1 and CD10 also increased concomitant with the loss of CD34, whereas expression of LECAM-1 diminished with CD34 downregulation. The differential expression of these antigens on early thymocytes (as well as the number of thymocytes displaying these patterns) was highly reproducible among the nine pediatric and four fetal specimens examined, suggesting a precise, stereotyped regulation of early differentiation events. Cell populations with antigen expression patterns suggestive of pluripotent stem cell (CD34high, CD38-), or non-T-lineage committed stem cells (CD34+, CD33+ or CD34+, CD19+) were not identified in either fetal or pediatric thymi (sensitivity = 1/10(4)). The presence of cells with the antigenic profile of the earliest CD34+ thymocytes was explored in human BM. Putative BM T-cell precursors with the appropriate phenotype (CD34+, CD7+, CD5+, CD2+, LECAM-1high) were readily identified in fetal specimens (constituting +/- 2% of the CD34+ population), but could not be reliably detected in adults. In contrast with thymi, only 13% of these cells expressed cytoplasmatic CD3, suggesting the presence of the immediate precursor of the putative prothymocyte population. This was further supported by the detection of CD34bright, CD7+, CD2-, CD5-, LECAM-1moderate cells in fetal specimens. Our results document the flow of cell surface differentiation during T-lymphopoiesis and suggest that T-lineage features are first acquired in the BM. The ability to reproducibly identify and isolate T-cell precursor populations of precisely defined maturational stage in marrow and thymus by multiparameter flow cytometry will facilitate characterization of the molecular events controlling T-lineage differentiation.

scholarly journals Abnormal thymic development, impaired immune function and gamma delta T cell lymphomas in a TL transgenic mouse strain.

1991 ◽  
Vol 174 (2) ◽  
pp. 351-362 ◽  
Author(s):  
Y Obata ◽  
O Taguchi ◽  
Y Matsudaira ◽  
H Hasegawa ◽  
N Hamasima ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
T Cell Differentiation ◽  
Gamma Delta ◽  
Thymic Development ◽  
T Cell Lymphomas

During derivation of transgenic mouse strains with various TL and TL/H-2 chimeric genes, one strain, Tg.Tlaa-3-1, introduced with a TL gene (Tlaa-3), was found to have an abnormal thymic T cell population and to develop a high incidence of T cell lymphomas. To investigate the etiology of the thymic abnormalities and of the lymphomas, the development of lymphoid organs in transgenic mice was studied. The thymus of these mice goes through three unusual successive events: perturbation of thymic development during embryogenesis, disappearance of thymocytes between day 14 and day 21 after birth, and subsequent proliferation of large blast-like cells. These events are associated with the abolishment of T cell receptor (TCR) alpha beta lineage of the T cell differentiation, leading to preponderance of cells belonging to the TCR gamma delta L3T4-Lyt-2- double negative (DN) lineage. Bone marrow transplantation and thymic graft experiments demonstrate that the abnormality resides in the bone marrow stem cells rather than in the thymic environment. The expression of TL antigen in the transgenic mice is greatly increased and TL is expressed in a wide range of T cells, including normally TL- DN cells and L3T4+ Lyt-2- and L3T4-Lyt-2+ single positive cells. These quantitative and qualitative abnormalities in TL expression most likely cause the abnormal T cell differentiation. The gamma delta DN cells migrate into peripheral lymphoid organs and constitute nearly 50% of peripheral T cells. Immune function of the transgenic mice is severely impaired, as T cell function is defective in antibody production to sheep red blood cells, in mixed lymphocyte culture reaction to allogenic spleen cells and also in stimulation with concanavalin A. These results indicate that the gamma delta cells are incapable of participating in these reactions. Molecular and serological analysis of T cell lymphomas reveal that they belong to the gamma delta lineage, suggesting that the gamma delta DN cells in this strain are susceptible to leukemic transformation. Based on cell surface phenotype and TCR expression of the DN thymocytes and T cell lymphomas, a map of the sequential steps involved in the differentiation of gamma delta DN cells is proposed.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Intrathymic transplantation of bone marrow–derived progenitors provides long-term thymopoiesis

Blood ◽  
2010 ◽  
Vol 115 (10) ◽  
pp. 1913-1920 ◽  
Author(s):  
Rita Vicente ◽  
Oumeya Adjali ◽  
Chantal Jacquet ◽  
Valérie S. Zimmermann ◽  
Naomi Taylor
Keyword(s):  
Bone Marrow ◽  
Cell Differentiation ◽  
T Cell ◽  
Large Population ◽  
Severe Combined Immunodeficiency ◽  
T Cell Differentiation ◽  
Hematopoietic Stem ◽  
Insufficient Entry ◽  
Deficient Mice

Abstract The sustained differentiation of T cells in the thymus cannot be maintained by resident intrathymic (IT) precursors and requires that progenitors be replenished from the bone marrow (BM). In patients with severe combined immunodeficiency (SCID) treated by hematopoietic stem cell transplantation, late T-cell differentiation defects are thought to be due to an insufficient entry of donor BM progenitors into the thymus. Indeed, we find that the intravenous injection of BM progenitors into nonconditioned ζ-chain–associated protein kinase 70 (ZAP-70)–deficient mice with SCID supports short- but not long-term thymopoiesis. Remarkably, we now show that the IT administration of these progenitors produces a significant level of donor-derived thymopoiesis for more than 6 months after transplantation. In contrast to physiologic thymopoiesis, long-term donor thymopoiesis was not due to the continued recruitment of progenitors from the BM. Rather, IT transplantation resulted in the unique generation of a large population of early c-Kithigh donor precursors within the thymus. These ZAP-70–deficient mice that received an IT transplant had a significantly increased prothymocyte niche compared with their untreated counterparts; this phenotype was associated with the generation of a medulla. Thus, IT administration of BM progenitors results in the filling of an expanded precursor niche and may represent a strategy for enhancing T-cell differentiation in patients with SCID.

scholarly journals Production of T lymphocyte colony-forming units from precursors in human long-term bone marrow cultures

Blood ◽  
1984 ◽  
Vol 64 (3) ◽  
pp. 656-661
Author(s):  
I Touw ◽  
B Lowenberg
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
T Lymphocyte ◽  
T Cell Differentiation ◽  
Colony Forming Units ◽  
Bone Marrow Cultures ◽  
Marrow Cultures

T cell differentiation in human marrow was studied in Dexter type long- term bone marrow cultures. In these cultures, T lymphocyte colony- forming units (TL-CFU), E rosette-forming cells (E+), and T3+, T4+, and T8+ cells (assayed by indirect immunofluorescence) were found to be present for at least 7 weeks. It was investigated whether the existence of T cells in long-term culture resulted from the persistence of inoculated T lymphocytes or from the production by immature progenitors. No significant numbers of E+, T3+, T4+, or T8+ cells were detected in cultures that were established from E+ lymphocyte-depleted bone marrow, indicating little or no production of T lymphocytes from E- negative precursors. On the other hand, bone marrow cells purged of E+ lymphocytes did not contain TL-CFU, but appeared to regain high numbers of TL-CFU during Dexter culture; this suggested that an earlier step in T cell differentiation may take place in this culture system. The generation of TL-CFU in the E-negative long-term marrow cultures only occurred when an adherent stroma layer had been established in the culture flask; it did not require added mitogens or detectable interleukin 2 in the culture medium. TL-CFU in fresh marrow (TL-CFU II) are mature (E+, T3+) T cells and are capable of producing helper (T4+) and suppressor/cytotoxic (T8+) phenotype cells in colonies. The TL-CFU newly formed in E-depleted Dexter cultures (TL-CFU I) are distinct from this population, as they are E-negative and give rise to colonies of the helper type only. T3 cell depletion of the marrow inoculum prior to culture did not prevent the appearance of TL-CFU I in long-term culture; this suggests that TL-CFU I are derived from an E- and T3- precursor (pre-TL-CFU).

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