Diversity, localization and (patho)physiology of mature lymphocyte populations in the bone marrow

Blood ◽  
2021 ◽  
Author(s):  
Christian M. Schürch ◽  
Chiara Caraccio ◽  
Martijn A. Nolte
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Plasma Cells ◽  
Cell Types ◽  
Lymphoid Organ ◽  
Lymphoid Cells ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Mature Lymphocyte ◽  
Lymphocyte Populations

The bone marrow (BM) is responsible for generating and maintaining lifelong output of blood and immune cells. Besides its key hematopoietic function, the BM acts as an important lymphoid organ, hosting a large variety of mature lymphocyte populations, including B-cells, T-cells, NK(T)-cells and innate lymphoid cells (ILCs). Many of these cell types are thought to only transiently visit the BM, but for others, like plasma cells and memory T-cells, the BM provides supportive niches that promote their long-term survival. Interestingly, accumulating evidence points towards an important role for mature lymphocytes in the regulation of hematopoietic stem cells (HSCs) and hematopoiesis in health and disease. In this review, we describe the diversity, migration, localization and function of mature lymphocyte populations in murine and human BM, focusing on their role in immunity and hematopoiesis. We also address how various BM lymphocyte subsets contribute to the development of aplastic anemia and immune thrombocytopenia, illustrating the complexity of these BM disorders, but also the underlying similarities and differences in their disease pathophysiology. Finally, we summarize the interactions between mature lymphocytes and BM resident cells in HSC transplantation and graft-versus-host disease. A better understanding of the mechanisms by which mature lymphocyte populations regulate BM function will likely improve future therapies for patients with benign and malignant hematological disorders.

scholarly journals Demonstration that Thy(lo) subsets of mouse bone marrow that express high levels of lineage markers are not significant hematopoietic progenitors

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3480-3490
Author(s):  
SJ Morrison ◽  
E Lagasse ◽  
IL Weissman
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Differentiation ◽  
Cell Types ◽  
Lymphoid Cells ◽  
Mouse Bone Marrow ◽  
Hematopoietic Stem ◽  
B Lineage ◽  
Proliferation Potential

We have been unable to reproduce experiments suggesting the existence of three lineage-restricted progenitor populations from mouse bone marrow. Thy1.1loMac-1+B220+ cells were reported to give rise to greatly expanded numbers of myeloid and lymphoid cells, while Thy1.1loMac- 1+B220- and Thy1.1loMac-1-B220+ cells were reported to be highly proliferative myeloid and B-lineage-restricted progenitors, respectively. Both Mac-1+ cell types appear to be much less frequent than previously reported, and we observed no activity consistent with their characterization as committed progenitors of expanded numbers of cells. The original identification of these populations may have resulted from a failure to distinguish bonafide signals from autofluorescent background and nonspecific staining. The progenitor activities originally associated with these populations may have been due to hematopoietic stem cell contamination. This study shows that low levels of Mac-1 are expressed on cells with multipotent progenitor activity. Thy1.1loB220+Mac-1- cells can be purified from bone marrow, but in these experiments they do not give rise to detectable levels of progeny on injection into lethally irradiated mice. Thy1.1loB220+Mac-1- cells appear to be pro-B cells without significant proliferation potential in vivo. The finding that the described populations do not have the reported progenitor activities leaves the pathways of stem cell differentiation open to further study.

scholarly journals Bone Marrow Memory CD8+ T Cells Play a Supporting Role in Hematopoiesis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4370-4370
Author(s):  
Sulima Geerman ◽  
Fernanda M Pascutti ◽  
Sudeep Bhushal ◽  
Martijn A. Nolte
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Conflicts Of Interest ◽  
Lymphoid Organ ◽  
Strong Impact ◽  
Activated T Cells ◽  
Hematopoietic Stem ◽  
Memory Cd8 T Cells

Abstract The bone marrow (BM) has an important function as primary lymphoid organ through the process of hematopoiesis. This process is sustained by hematopoietic stem cells (HSCs) and their life-long production of new blood cells, which is made possible by their unique ability to self-renew. Next to this, BM also functions as a secondary lymphoid organ, as it can mediate primary T cell responses against invading pathogens. We and others have shown that activated T cells can influence the hematopoietic process through the production of pro-inflammatory cytokines. This indicates that adaptive immune responses and hematopoiesis are intertwined in the BM, though most of the cellular and molecular interactions that occur during this crosstalk are yet unknown. Based on previous observations that T cell deficient mice have altered hematopoiesis and that depletion of T cells from allogeneic BM grafts compromises HSC engraftment, we questioned to what extent BM T cells can directly affect the function of HSCs. To test this, we sorted and co-cultured murine BM T cells with HSCs (Lin-Sca-1+c-Kit+CD48-CD150+). We found that particularly BM CD8+ central memory (CD44+CD62L+) T cells (Tcm) enhance the capacity of HSCs to self-renew. Furthermore, we found that TCR-transgenic mice, which do not have memory T cells, have lower numbers of HSCs, which could subsequently be increased by transferring BM CD8+ Tcm. Remarkably, an increase in HSC numbers was also observed when HSCs were cultured with only supernatant derived from BM CD8+ Tcm. Moreover, HSCs cultured with supernatant from BM CD8+ Tcm and later transplanted in myeloablated hosts displayed a strongly enhanced ability to restore hematopoiesis. Importantly, the strong impact of BM T cells on HSCs was not only apparent in the steady state situation, but also following a viral infection with either acute or chronic lymphocytic choriomeningitis virus (LCMV). We could establish that both acute and chronic LCMV-specific CD8+ T cells or supernatant from these cells could increase the HSC self-renewal capacity. In conclusion, our findings demonstrate that BM memory CD8+ T cells can positively influence the function of HSC through soluble mediators. We postulate that this process is particularly relevant after immune activation, in order to protect and/or restore the HSC pool and the subsequent hematopoietic recovery. We are currently using a proteomics approach to identify these soluble mediator produced by CD8+ T cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Broad-Spectrum Antibiotics Deplete Bone Marrow Regulatory T Cells

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 277
Author(s):  
Hyojeong Han ◽  
Hannah Yan ◽  
Katherine Y. King
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Regulatory T Cells ◽  
Intestinal Microbiota ◽  
Clinical Care ◽  
Antibiotic Use ◽  
Cell Types ◽  
Bone Marrow Suppression ◽  
Antibiotic Administration ◽  
Hematopoietic Stem

Bone marrow suppression, including neutropenia, is a major adverse effect of prolonged antibiotic use that impairs the clinical care and outcomes of patients with serious infections. The mechanisms underlying antibiotic-mediated bone marrow suppression remain poorly understood, with initial evidence indicating that depletion of the intestinal microbiota is an important factor. Based on our earlier studies of blood and bone marrow changes in a mouse model of prolonged antibiotic administration, we studied whether changes in megakaryocytes or regulatory T cells (Tregs), two cell types that are critical in the maintenance of hematopoietic stem cells, contribute to antibiotic-mediated bone marrow suppression. Despite increased platelet numbers, megakaryocytes were unchanged in the bone marrow of antibiotic-treated mice; however, Tregs were found to be significantly depleted. Exogenous addition of Tregs was insufficient to rescue the function of bone marrow from antibiotic-treated mice in both colony formation and transplantation assays. These findings indicate that the intestinal microbiota support normal Treg development to protect healthy hematopoiesis, but that the restoration of Tregs alone is insufficient to restore normal bone marrow function.

scholarly journals Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression

Leukemia ◽  
2021 ◽  
Author(s):  
Julia Dahlhoff ◽  
Hannah Manz ◽  
Tim Steinfatt ◽  
Julia Delgado-Tascon ◽  
Elena Seebacher ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
Plasma Cells ◽  
Nk Cell ◽  
Hematopoietic Stem ◽  
Treg Depletion

AbstractMultiple myeloma remains a largely incurable disease of clonally expanding malignant plasma cells. The bone marrow microenvironment harbors treatment-resistant myeloma cells, which eventually lead to disease relapse in patients. In the bone marrow, CD4+FoxP3+ regulatory T cells (Tregs) are highly abundant amongst CD4+ T cells providing an immune protective niche for different long-living cell populations, e.g., hematopoietic stem cells. Here, we addressed the functional role of Tregs in multiple myeloma dissemination to bone marrow compartments and disease progression. To investigate the immune regulation of multiple myeloma, we utilized syngeneic immunocompetent murine multiple myeloma models in two different genetic backgrounds. Analyzing the spatial immune architecture of multiple myeloma revealed that the bone marrow Tregs accumulated in the vicinity of malignant plasma cells and displayed an activated phenotype. In vivo Treg depletion prevented multiple myeloma dissemination in both models. Importantly, short-term in vivo depletion of Tregs in mice with established multiple myeloma evoked a potent CD8 T cell- and NK cell-mediated immune response resulting in complete and stable remission. Conclusively, this preclinical in-vivo study suggests that Tregs are an attractive target for the treatment of multiple myeloma.

scholarly journals The Bone Marrow as Sanctuary for Plasma Cells and Memory T-Cells: Implications for Adaptive Immunity and Vaccinology

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1508
Author(s):  
Stefan A. Slamanig ◽  
Martijn A. Nolte
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Plasma Cells ◽  
Memory T Cells ◽  
Memory Cell ◽  
Immunological Memory ◽  
Lymphoid Organ ◽  
Human Immune System ◽  
Extrinsic Factors ◽  
Holistic Understanding

The bone marrow (BM) is key to protective immunological memory because it harbors a major fraction of the body’s plasma cells, memory CD4+ and memory CD8+ T-cells. Despite its paramount significance for the human immune system, many aspects of how the BM enables decade-long immunity against pathogens are still poorly understood. In this review, we discuss the relationship between BM survival niches and long-lasting humoral immunity, how intrinsic and extrinsic factors define memory cell longevity and show that the BM is also capable of adopting many responsibilities of a secondary lymphoid organ. Additionally, with more and more data on the differentiation and maintenance of memory T-cells and plasma cells upon vaccination in humans being reported, we discuss what factors determine the establishment of long-lasting immunological memory in the BM and what we can learn for vaccination technologies and antigen design. Finally, using these insights, we touch on how this holistic understanding of the BM is necessary for the development of modern and efficient vaccines against the pandemic SARS-CoV-2.

scholarly journals Demonstration that Thy(lo) subsets of mouse bone marrow that express high levels of lineage markers are not significant hematopoietic progenitors

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3480-3490 ◽  
Author(s):  
SJ Morrison ◽  
E Lagasse ◽  
IL Weissman
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Differentiation ◽  
Cell Types ◽  
Lymphoid Cells ◽  
Mouse Bone Marrow ◽  
Hematopoietic Stem ◽  
B Lineage ◽  
Proliferation Potential

Abstract We have been unable to reproduce experiments suggesting the existence of three lineage-restricted progenitor populations from mouse bone marrow. Thy1.1loMac-1+B220+ cells were reported to give rise to greatly expanded numbers of myeloid and lymphoid cells, while Thy1.1loMac- 1+B220- and Thy1.1loMac-1-B220+ cells were reported to be highly proliferative myeloid and B-lineage-restricted progenitors, respectively. Both Mac-1+ cell types appear to be much less frequent than previously reported, and we observed no activity consistent with their characterization as committed progenitors of expanded numbers of cells. The original identification of these populations may have resulted from a failure to distinguish bonafide signals from autofluorescent background and nonspecific staining. The progenitor activities originally associated with these populations may have been due to hematopoietic stem cell contamination. This study shows that low levels of Mac-1 are expressed on cells with multipotent progenitor activity. Thy1.1loB220+Mac-1- cells can be purified from bone marrow, but in these experiments they do not give rise to detectable levels of progeny on injection into lethally irradiated mice. Thy1.1loB220+Mac-1- cells appear to be pro-B cells without significant proliferation potential in vivo. The finding that the described populations do not have the reported progenitor activities leaves the pathways of stem cell differentiation open to further study.

scholarly journals Innervation of the Thymus Gland: A Short Review of Function and Histology

2018 ◽  
Vol 2 (2) ◽  
pp. 01-02
Author(s):  
Bolaji Babalola
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
Young Animal ◽  
Cell Types ◽  
Short Review ◽  
Systemic Circulation ◽  
Lymphoid Organ ◽  
Lymphoid Cells ◽  
Symbiotic Interaction

The thymus, a primary lymphoid organ and the initial site for development of T cell immunological function, is morphologically similar across species. It is actually an epithelial organ in which its epithelial cells provide a framework containing T cells as well as smaller numbers of other lymphoid cells. A symbiotic interaction exists between the thymic microinvironment and developing T cells, and the specificity of T cell release into the systemic circulation is under thymic control. The thymic cortex in a young animal is heavily populated by developing T cells along with a smaller proportion of associated epithelial cells. Larger, more mature T cells are found in the medulla where epithelial and other cell types are more abundant. Understanding normal morphological features of the thymus and their perturbations provides a cornerstone to assessing immune system function.

scholarly journals Bone marrow stromal cells from MDS and AML patients show increased adipogenic potential with reduced Delta-like-1 expression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marie-Theresa Weickert ◽  
Judith S. Hecker ◽  
Michèle C. Buck ◽  
Christina Schreck ◽  
Jennifer Rivière ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Fate ◽  
Stromal Cells ◽  
Adipogenic Differentiation ◽  
Cell Types ◽  
Bone Marrow Niche ◽  
Differentiation Potential ◽  
Hematopoietic Stem ◽  
Bm Niche

AbstractMyelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell disorders with a poor prognosis, especially for elderly patients. Increasing evidence suggests that alterations in the non-hematopoietic microenvironment (bone marrow niche) can contribute to or initiate malignant transformation and promote disease progression. One of the key components of the bone marrow (BM) niche are BM stromal cells (BMSC) that give rise to osteoblasts and adipocytes. It has been shown that the balance between these two cell types plays an important role in the regulation of hematopoiesis. However, data on the number of BMSC and the regulation of their differentiation balance in the context of hematopoietic malignancies is scarce. We established a stringent flow cytometric protocol for the prospective isolation of a CD73+ CD105+ CD271+ BMSC subpopulation from uncultivated cryopreserved BM of MDS and AML patients as well as age-matched healthy donors. BMSC from MDS and AML patients showed a strongly reduced frequency of CFU-F (colony forming unit-fibroblast). Moreover, we found an altered phenotype and reduced replating efficiency upon passaging of BMSC from MDS and AML samples. Expression analysis of genes involved in adipo- and osteogenic differentiation as well as Wnt- and Notch-signalling pathways showed significantly reduced levels of DLK1, an early adipogenic cell fate inhibitor in MDS and AML BMSC. Matching this observation, functional analysis showed significantly increased in vitro adipogenic differentiation potential in BMSC from MDS and AML patients. Overall, our data show BMSC with a reduced CFU-F capacity, and an altered molecular and functional profile from MDS and AML patients in culture, indicating an increased adipogenic lineage potential that is likely to provide a disease-promoting microenvironment.

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