Extra-Thymic Physiological T Lineage Progenitor Activity Is Exclusively Confined to Cells Expressing either CD127, CD90, or High Levels of CD117

Saran, Namita; Pommerencke, Jens; Witzlau, Katrin; Regelin, Malte; Krueger, Andreas

doi:10.1371/journal.pone.0030864

Cited by 4 publications

(4 citation statements)

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“…Although direct precursor-progeny relationships between these progenitor populations still remain elusive to some extent, there is substantial evidence that CLPs form the main source of B cell development in the bone marrow (BM) (1). In contrast, T cell development can probably be sustained by multiple thymus-colonizing BM-derived progenitor populations with different degrees of lineage restriction including MPPs, CLPs, and potentially others (2)(3)(4)(5). Inside the thymus T cell progenitors undergo a series of differentiation steps starting with the process of T lineage commitment, which is controlled by a network of transcription factors and sustained by cytokines such as IL-7 and stem cell factor (6).…”

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confidence: 99%

Responsiveness of Developing T Cells to IL-7 Signals Is Sustained by miR-17∼92

Regelin

Blume

Pommerencke

et al. 2015

The Journal of Immunology

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miRNAs regulate a large variety of developmental processes including development of the immune system. T cell development is tightly controlled through the interplay of transcriptional programs and cytokine-mediated signals. However, the role of individual miRNAs in this process remains largely elusive. In this study, we demonstrated that hematopoietic cell–specific loss of miR-17∼92, a cluster of six miRNAs implicated in B and T lineage leukemogenesis, resulted in profound defects in T cell development both at the level of prethymic T cell progenitors as well as intrathymically. We identified reduced surface expression of IL-7R and concomitant limited responsiveness to IL-7 signals as a common mechanism resulting in reduced cell survival of common lymphoid progenitors and thymocytes at the double-negative to double-positive transition. In conclusion, we identified miR-17∼92 as a critical modulator of multiple stages of T cell development.

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confidence: 99%

Responsiveness of Developing T Cells to IL-7 Signals Is Sustained by miR-17∼92

Regelin

Blume

Pommerencke

et al. 2015

The Journal of Immunology

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“…The thymus supports a proper T cell ontogeny due to the presence of specialized epithelial cells, resulting in the export of naïve CD45RA + CD62L + T cells that follows the recruitment of progenitors from bone marrow [1] .…”

Section: Introductionmentioning

confidence: 99%

Molecular Evidence for a Thymus-Independent Partial T Cell Development in a FOXN1−/− Athymic Human Fetus

et al. 2013

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The thymus is the primary organ able to support T cell ontogeny, abrogated in FOXN1−/− human athymia. Although evidence indicates that in animal models T lymphocytes may differentiate at extrathymic sites, whether this process is really thymus-independent has still to be clarified. In an athymic FOXN1−/− fetus, in which we previously described a total blockage of CD4+ and partial blockage of CD8+ cell development, we investigated whether intestine could play a role as extrathymic site of T-lymphopoiesis in humans. We document the presence of few extrathymically developed T lymphocytes and the presence in the intestine of CD3+ and CD8+, but not of CD4+ cells, a few of them exhibiting a CD45RA+ naïve phenotype. The expression of CD3εεpTα, RAG1 and RAG2 transcripts in the intestine and TCR gene rearrangement was also documented, thus indicating that in humans the partial T cell ontogeny occurring at extrathymic sites is a thymus- and FOXN1-independent process.

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“…The apparent discrepancy between dynamic expression but lack of a regulatory function in the thymus led us to conclude that miR-21 is rather fine-tuning T-cell responses than controlling a developmental event. hochspezialisierten Organ, dem Thymus, statt (Miller, 1961) Vorarbeiten unserer Gruppe haben sich besonders auf die Identifizierung und Charakterisierung von Vorläuferzellen spezialisiert (Krueger und Boehmer, 2007;Saran et al, 2010;Saran et al, 2012). Insbesondere konnte dabei gezeigt werden, dass der Eintritt in den Thymus von zwei Chemokinrezeptoren, CCR7 und CCR9, abhängt (Krueger et al, 2010).…”

Section: Discussionunclassified

“…Bone-marrow derived progenitor cells with the capacity to colonize the thymus were studied intensively over the past years in human and mouse. Interestingly, these so-called thymus seeding progenitors (TSPs) represent a heterogenous mixture of cells with different characteristics including multipotent progenitors (MPPs), common lymphoid progenitors (CLPs) and CLP-like cells as well as T-lineage pre-committed progenitors (Igarashi et al, 2002;Perry et al, 2004;Adolfsson et al, 2005;Rossi et al, 2005;Scimone et al, 2006;Bhandoola et al, 2007;Krueger and Boehmer, 2007;Bell and Bhandoola, 2008;Wada et al, 2008;Serwold et al, 2009;Schlenner et al, 2010;Krueger, 2011;Saran et al, 2012;Luis et al, 2016;Lavaert et al, 2020). These TSPs circulate in the blood and enter the thymus via large venules.…”

Section: T-cell Development: a Journey Through The Thymusmentioning

confidence: 99%

Molecular and cellular control of intrathymic T-Cell development

Kunze‐Schumacher¹

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T cell development is a highly dynamic and stepwise process comprimising T lineage commitment, T cell receptor (TCR) gene rearrangements and subsequent selection. From a quantitative point of view, only a few hundred progenitor cells migrate from the bone marrow into the thymus. Developing thymocytes (termed double negative (DN), CD4 CD8 ) can be further divided into DN1 4 cells based on the expression of CD25 and CD44. These developmental events are interspersed by proliferative bursts which ultimately lead to the generation of millions of double positive (DP, CD4+CD8+) thymocytes that then undergo selection. As a consequence, a proportion of naïve T cells evolves to ensure adaptive, but not autoreactive immunity. Previous studies of our lab focused on the quantification of thymus colonization and identified thymus entry to be dependent on expression of the chemokine receptors CCR7 and CCR9 (Krueger et al., 2010; Ziętara et al., 2015). CCR7/9 double knockout (DKO) mice are almost completely devoid of the most immature thymocyte populations (DN1 and DN2), but show near normal DN3 cellularity. Interestingly, a similar defect during early development but a virtually complete recovery of later stages and total thymocyte numbers was also observed in thymi of miR 17~92 deficient mice. Here, a failure of prethymic IL 7 signaling dampens early T cell development (Regelin et al., 2015). For this reason, we hypothesized a tight regulation of thymocyte population size through alterations in the underlying cell cycle kinetics. In this thesis, we employed in vivo single and dual nucleoside pulse labeling combined with determination of DNA replication over time in different WT thymocyte subsets at steady state. Based on this, we assessed alterations in cell cycle kinetics of CCR7/9 and miR 17~92 defcicient mice and identified compensatory mechanisms of thymocytes on the level of cell cycle phase distribution and cell cycle speed. In addition, single cell RNA sequencing helped to obtain information on cell cycle dynamics of early thymocyte subsets, exemplarily shown for WT and CCR7/9 DKO mice. Lastly, we performed cell cycle analyses in a model of endogenous thymic repair upon sublethal total body irradiation which provided insight into intrathymic cell cycle regulation as an adjustable system to re establish normal thymus cellularity. In the second part of the thesis, we addressed the role of miR 21 in the thymus. In various studies, we and others identified miRNAs as key posttranscriptional regulators of the immune system and especially for T cell development (Regelin et al. 2015; Mildner et al. 2017; Li et al. 2007; Ebert et al. 2009; Ziętara et al. 2013; Schaffert et al. 2015). The dynamic expression of miR 21 during T cell development (Neilson et al. 2007; Kirigin et al. 2012; Kuchen et al. 2010) prompted us to hypothesize that miR 21 has a regulatory function in the thymus. A miR 21 knockout mouse model allowed us to study the role of this miRNA for the development of T cells in the thymus and the maintenance of T cells in the periphery. In addition, we performed competitive bone marrow chimera experiments in the context of miR 21 deficiency and overexpression. Further insights were provided by exploring the function of miR 21 in negative selection in vivo as well as in T cell differentiation in coculture experiments in vitro. To unravel implications of miR 21 to regulate cellular stress responses, we assessed the contribution of miR 21 in a model of endogenous regeneration of the thymus after sublethal irradiation. We could not provide evidence for a prominent role for miR 21 during T cell development. Together, our experiments revealed that miR 21 is largely dispensable for physiologic T cell development despite high and dynamic expression in the thymus (Kunze Schumacher et al., 2018). The apparent discrepancy between dynamic expression but lack of a regulatory function in the thymus led us to conclude that miR 21 is rather fine tuning T cell responses than controlling a developmental event.

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Extra-Thymic Physiological T Lineage Progenitor Activity Is Exclusively Confined to Cells Expressing either CD127, CD90, or High Levels of CD117

Cited by 4 publications

References 27 publications

Responsiveness of Developing T Cells to IL-7 Signals Is Sustained by miR-17∼92

Responsiveness of Developing T Cells to IL-7 Signals Is Sustained by miR-17∼92

Molecular Evidence for a Thymus-Independent Partial T Cell Development in a FOXN1−/− Athymic Human Fetus

Molecular and cellular control of intrathymic T-Cell development

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