Tracking migration during human T cell development

Halkias, Joanna; Melichar, Heather J.; Taylor, Kayleigh T.; Robey, Ellen

doi:10.1007/s00018-014-1607-2

Cited by 31 publications

(34 citation statements)

References 142 publications

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“…Included in this list are the reduced levels of many chemokines necessary for thymocyte recruitment and trafficking within the cortex and medulla ( Table 2). Thus, miR-205 partly supports thymopoiesis by maintaining and/or re-establishing chemokine gradients following stress (42,43). The localization of the cTECs and mTECs were not disrupted following stress, rather the thymo- cytes were mislocalized.…”

Section: Discussionmentioning

confidence: 96%

MicroRNA-205 Maintains T Cell Development following Stress by Regulating Forkhead Box N1 and Selected Chemokines

Hoover¹,

Dozmorov²,

MacLeod³

et al. 2016

Journal of Biological Chemistry

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The thymus, an organ responsible for T cell development, is one of the more stress-sensitive tissues in the body. Stress, in the form of infections, radiation exposure, and steroids, impairs thymic epithelial cell (TEC) functions and induces the programmed cell death of immature thymocytes. MicroRNAs are small noncoding RNAs involved in tissue repair and homeostasis, with several supporting T cell development. We report that miR-205, an epithelial-specific miR, maintains thymopoiesis following inflammatory perturbations. Thus, the activation of diverse pattern recognition receptors in mice causes a more severe thymic hypoplasia and delayed T cell recovery when miR-205 is conditionally ablated in TECs. Gene expression comparisons in the TECs with/without miR-205 revealed a significant differential regulation of chemokine/chemokine receptor pathways, antigen processing components, and changes in the Wnt signaling system. This was partly a consequence of reduced expression of the transcriptional regulator of epithelial cell function, Forkhead Box N1 (Foxn1), and its two regulated targets, stem cell factor and ccl25, following stress. miR-205 mimics supplemented into miR-205-deficient fetal thymic organ cultures restored Foxn1 expression along with ccl25 and stem cell factor A number of putative targets of miR-205 were up-regulated in TECs lacking miR-205, consistent with an important role for this miR in supporting T cell development in response to stress.

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Section: Discussionmentioning

confidence: 96%

MicroRNA-205 Maintains T Cell Development following Stress by Regulating Forkhead Box N1 and Selected Chemokines

Hoover¹,

Dozmorov²,

MacLeod³

et al. 2016

Journal of Biological Chemistry

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“…Human T-cell development requires that developmental intermediates undergo specific maturation stages within distinct niches of the thymus, resulting in a tight coupling of thymocyte differentiation with migration and cellular interactions. 43 To further examine the degree of interspecies cross-talk that allows human T cells to develop in a mouse thymic environment, we studied the behavior of human thymocytes within the humanized mouse thymus. Neonatal chimera NSG or NSG HLA-A2 tg mice were reconstituted with HLA-A2 − cord blood CD34 + hematopoietic progenitors transduced at a low multiplicity of infection with a lentivirus expressing GFP (Lenti-GFP).…”

Section: Human Thymocyte Migration and Cellular Interactions In A Moumentioning

confidence: 99%

Conserved and divergent aspects of human T‐cell development and migration in humanized mice

et al. 2015

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Humanized mice represent an important model to study the development and function of the human immune system. While it is known that mouse thymic stromal cells can support human T-cell development, the extent of interspecies cross-talk and the degree to which these systems recapitulate normal human T-cell development remain unclear. To address these questions, we compared conventional and non-conventional T-cell development in a neonatal chimera humanized mouse model with that seen in human fetal and neonatal thymus samples, and also examined the impact of a human HLA-A2 transgene expressed by the mouse stroma. Given that dynamic migration and cell–cell interactions are essential for T-cell differentiation, we also studied the intrathymic migration pattern of human thymocytes developing in a murine thymic environment. We found that both conventional T-cell development and intra-thymic migration patterns in humanized mice closely resemble human thymopoiesis. Additionally, we show that developing human thymocytes engage in short, serial interactions with other human hematopoietic-derived cells. However, non-conventional T-cell differentiation in humanized mice differed from both fetal and neonatal human thymopoiesis, including a marked deficiency of Foxp3+ T-cell development. These data suggest that although the murine thymic microenvironment can support a number of aspects of human T-cell development, important differences remain, and additional human-specific factors may be required.

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“…As a result, developing thymocytes encounter specific signals at specific locations in the thymus (9). The OP9-DL1 coculture system lacks the typical thymus architecture that is required for proper T-cell development.…”

Section: Introductionmentioning

confidence: 99%

Loss of CD44dim Expression from Early Progenitor Cells Marks T-Cell Lineage Commitment in the Human Thymus

Canté-Barrett

Mendes

et al. 2017

Front. Immunol.

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Human T-cell development is less well studied than its murine counterpart due to the lack of genetic tools and the difficulty of obtaining cells and tissues. Here, we report the transcriptional landscape of 11 immature, consecutive human T-cell developmental stages. The changes in gene expression of cultured stem cells on OP9-DL1 match those of ex vivo isolated murine and human thymocytes. These analyses led us to define evolutionary conserved gene signatures that represent pre- and post-αβ T-cell commitment stages. We found that loss of dim expression of CD44 marks human T-cell commitment in early CD7+CD5+CD45dim cells, before the acquisition of CD1a surface expression. The CD44−CD1a− post-committed thymocytes have initiated in frame T-cell receptor rearrangements that are accompanied by loss of capacity to differentiate toward myeloid, B- and NK-lineages, unlike uncommitted CD44dimCD1a− thymocytes. Therefore, loss of CD44 represents a previously unrecognized human thymocyte stage that defines the earliest committed T-cell population in the thymus.

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Tracking migration during human T cell development

Cited by 31 publications

References 142 publications

MicroRNA-205 Maintains T Cell Development following Stress by Regulating Forkhead Box N1 and Selected Chemokines

MicroRNA-205 Maintains T Cell Development following Stress by Regulating Forkhead Box N1 and Selected Chemokines

Conserved and divergent aspects of human T‐cell development and migration in humanized mice

Loss of CD44dim Expression from Early Progenitor Cells Marks T-Cell Lineage Commitment in the Human Thymus

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