Identification of checkpoints in human T-cell development using severe combined immunodeficiency stem cells

Wiekmeijer, Anna-Sophia; Pike-Overzet, Karin; IJspeert, Hanna; Brugman, Martijn H.; Wolvers-Tettero, I. L. M.; Lankester, Arjan C.; Bredius, Robbert G. M.; Dongen, Jacques J. M. van; Fibbe, Willem E.; Langerak, Anton W.; Burg, Mirjam van der

doi:10.1016/j.jaci.2015.08.022

Cited by 28 publications

(35 citation statements)

References 47 publications

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“…For the other types of SCID, using confirmed null mutants, we observed a complete lack of peripheral T cells, which could be attributed to a severe, early, and complete block in thymic development. 78 The arrests in T cell development observed for the different types of SCID demonstrate a hierarchy in TCR rearrangement and the corresponding phenotypes (Fig. 3).…”

Section: Human Scid As a System To Understand Functional Requirementsmentioning

confidence: 93%

“…TCR rearrangements were functionally required at the CD4 -CD8 -CD7 + CD5 + stage, given the developmental block and extent of rearrangements in mice transplanted with Artemis-SCID. 78 The blocks in development, occurring in the immature DN stages, are much earlier than previously assumed on the basis of mouse data 80 or gene expression profiling. 5 They indicate that human ␤ selection may occur as early as the CD34 + CD1a -CD7 + CD5 + stage.…”

Section: Human Scid As a System To Understand Functional Requirementsmentioning

confidence: 96%

“…67 Using this system, we transplanted human HSCs of SCID patients with known gene defects that affect development of T cells. 78 However, the nature of the defects and the stage at which these "experiments of nature" affect T cell development have thus far been unknown. We have engrafted NSG mice with HSPCs isolated from BM of SCID patients with mutations in different genes, including ADA-SCID, Artemis (DCLRE1C)-SCID, IL7RA-SCID, and IL2RG-SCID.…”

Section: Human Scid As a System To Understand Functional Requirementsmentioning

confidence: 99%

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The functional relationship between hematopoietic stem cells and developing T lymphocytes

Wiekmeijer

Brugman

Pike-Overzet

2016

Annals of the New York Academy of Sciences

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In contrast to all other blood and immune cells, T lymphocytes do not develop in the bone marrow (BM), but in the specialized microenvironment provided by the thymus. Similar to the other lineages, however, all T cells arise from multipotent hematopoietic stem cells (HSCs) that reside in the BM. Not all HSCs give rise to T cells; but how many and what kind of developmental checkpoints are located along this intricate differentiation path is the subject of intense research. Traditionally, this process has been studied almost exclusively using mouse cells, but recent advances in immunodeficient mouse models, high-speed cell sorting, lentiviral transduction protocols, and deep sequencing techniques have allowed these questions to be addressed using human cells. Here we review the process of thymic seeding by BM-derived cells and T cell commitment in humans, discussing recent insights into the clonal composition of the thymus and the definition of developmental checkpoints, on the basis of insights from human severe combined immunodeficiency patients.

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Section: Human Scid As a System To Understand Functional Requirementsmentioning

confidence: 93%

Section: Human Scid As a System To Understand Functional Requirementsmentioning

confidence: 96%

Section: Human Scid As a System To Understand Functional Requirementsmentioning

confidence: 99%

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The functional relationship between hematopoietic stem cells and developing T lymphocytes

Wiekmeijer

Brugman

Pike-Overzet

2016

Annals of the New York Academy of Sciences

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“…X-SCID is caused by mutations in the gene encoding the g common chain shared by several cytokine receptors, including the interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors. In view of these receptors' roles in hematopoiesis, X-SCID is characterized by an early block in T and NK cell differentiation, the complete absence of T and NK cells and normal-to-elevated numbers of poorly functional, mature B cells [12,13].…”

Section: Severe Combined Immunodeficienciesmentioning

confidence: 99%

Gene Therapy with Hematopoietic Stem Cells: The Diseased Bone Marrow's Point of View

Cavazzana

Ribeil

Lagresle-Peyrou

et al. 2017

Stem Cells and Development

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When considering inherited diseases that can be treated by gene transfer into hematopoietic stem cells (HSCs), there are only two in which the HSC and progenitor cell distribution inside the bone marrow and its microenvironment are exactly the same as in a healthy subject: metachromatic leukodystrophy (MLD) and adrenoleukodystrophy (ALD). In all other settings [X-linked severe combined immunodeficiency (X-SCID), adenosine deaminase deficiency, Wiskott-Aldrich syndrome, and b-hemoglobinopathies], the bone marrow content of the different stem and precursor cells and the cells' relationship with the stroma have very specific characteristics. These peculiarities can influence the cells' harvesting and behavior in culture, and the postgraft uptake and further behavior of the gene-modified hematopoietic/precursor cells. In the present mini-review, we shall briefly summarize these characteristics and outline the possible consequences and challenges.

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“…Studies on primary immunodeficiency (61, 62), and on the immunological reconstitution achieved by the appropriate correction of these defects with HSCT (63), gene therapy (64–66), or thymus transplantation (67, 68), have been instrumental to better understand T-cell development. As an illustrative example of the knowledge that can be gathered from these clinical cases, we showed that the activity of thymus explants, evaluated by sj/βTREC ratio, drastically diminished 3 years post-thymic transplantation in a case of athymia due to FOXN1 deficiency (68).…”

Section: Establishment Of the Naïve Cd4+ T-cell Compartmentmentioning

confidence: 99%

Establishment and Maintenance of the Human Naïve CD4+ T-Cell Compartment

Silva¹,

Sousa

2016

Front. Pediatr.

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The naïve CD4+ T-cell compartment is considered essential to guarantee immune competence throughout life. Its replenishment with naïve cells with broad diverse receptor repertoire, albeit with reduced self-reactivity, is ensured by the thymus. Nevertheless, cumulative data support a major requirement of post-thymic proliferation both for the establishment of the human peripheral naïve compartment during the accelerated somatic growth of childhood, as well as for its lifelong maintenance. Additionally, a dynamic equilibrium is operating at the cell level to fine-tune the T-cell receptor threshold to activation and survival cues, in order to counteract the continuous naïve cell loss by death or conversion into memory/effector cells. The main players in these processes are low-affinity self-peptide/MHC and cytokines, particularly IL-7. Moreover, although naïve CD4+ T-cells are usually seen as a homogeneous population regarding stage of maturation and cell differentiation, increasing evidence points to a variety of phenotypic and functional subsets with distinct homeostatic requirements. The paradigm of cells committed to a distinct lineage in the thymus are the naïve regulatory T-cells, but other functional subpopulations have been identified based on their time span after thymic egress, phenotypic markers, such as CD31, or cytokine production, namely IL-8. Understanding the regulation of these processes is of utmost importance to promote immune reconstitution in several clinical settings, namely transplantation, persistent infections, and aging. In this mini review, we provide an overview of the mechanisms underlying human naïve CD4+ T-cell homeostasis, combining clinical data, experimental studies, and modeling approaches.

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Identification of checkpoints in human T-cell development using severe combined immunodeficiency stem cells

Cited by 28 publications

References 47 publications

The functional relationship between hematopoietic stem cells and developing T lymphocytes

The functional relationship between hematopoietic stem cells and developing T lymphocytes

Gene Therapy with Hematopoietic Stem Cells: The Diseased Bone Marrow's Point of View

Establishment and Maintenance of the Human Naïve CD4+ T-Cell Compartment

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