In vivo fate mapping identifies pre-TCRα expression as an intra- and extrathymic, but not prethymic, marker of T lymphopoiesis

Luche, Hervé; Rao, Tata Nageswara; Kumar, Suresh; Tasdogan, Alpaslan; Beckel, Franziska; Blum, Carmen; Martins, Vera C.; Rodewald, Hans Reimer; Fehling, Hans Jörg

doi:10.1084/jem.20122609

Cited by 22 publications

(26 citation statements)

References 67 publications

(118 reference statements)

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“…Erk2 was conditionally ablated in T lineage progenitors using Ptcra-Cre (Luche et al, 2013), while Erk1 was ablated in the germline (Fischer et al, 2005). Ptcra-Cre mediated ablation of Erk2 began in DN3 (CD4 − CD8 − CD44 − CD25 + ) thymocytes and was complete in DN4 (CD4 − CD8 − CD44 − CD25 − ) and γδTCR + thymocytes (Figure S1C).…”

Section: Resultsmentioning

confidence: 99%

Noncanonical Mode of ERK Action Controls Alternative αβ and γδ T Cell Lineage Fates

et al. 2014

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SUMMARY Gradations in ERK signaling have been implicated in essentially every developmental checkpoint or differentiation process encountered by lymphocytes. Yet, despite intensive effort, the molecular basis by which differences in ERK activation specify alternative cell fates remains poorly understood. We report here that differential ERK signaling controls lymphoid fate specification through an alternative mode of action. While ERK phosphorylates most substrates, such as Rsk, by targeting them through its D-domain, this well-studied mode of ERK action was dispensable for development of γδ T cells. Instead, development of γδ T cells was dependent upon an alternative mode of action mediated by the DEF-binding pocket (DBP) of ERK. This domain enabled ERK to bind a distinct and select set of proteins required for specification of the γδ fate. These data provide the first in vivo demonstration for the role of DBP-mediated interactions in orchestrating alternate ERK-dependent developmental outcomes.

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Section: Resultsmentioning

confidence: 99%

Noncanonical Mode of ERK Action Controls Alternative αβ and γδ T Cell Lineage Fates

et al. 2014

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“…These findings are consistent with recent fate mapping experiments. 11,12,16 Liberation of niches occupied by tDCs generates a permissive state for T-lineage progenitors to adopt an alternative fate, although the extent to which this alternative pathway of DC development operates in different physiological scenarios remains to be investigated. Of note, the presence of immunoglobulin gene rearrangements exclusively in thymic but not in other cDC subsets suggests, at least in some instances, that tDCs might be generated through this alternative pathway.…”

Section: Discussionmentioning

confidence: 99%

“…11 Consistently, fate mapping based on Ptcra expression showed that tDCs were not derived from T-lineage committed cells. 12 An intrathymic DC progenitor population that is likely to be of independent origin from ETPs was identified in mice expressing a CD207(Langerin)-green fluorescent protein (GFP) reporter gene. 13 In addition, these progenitors already expressed CD11c and low levels of MHC-II, and appeared therefore to be more mature than peripheral pre-DCs of the canonical DC developmental pathway.…”

Section: Introductionmentioning

confidence: 99%

Limited niche availability suppresses murine intrathymic dendritic-cell development from noncommitted progenitors

Łyszkiewicz

Zie̜tara

Föhse

et al. 2015

Blood

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Key Points• DCs and T-lineage cells in the thymus have separate origins.• Availability of microenvironmental niches in the thymus determines lineage fate.The origins of dendritic cells (DCs) and other myeloid cells in the thymus have remained controversial. In this study, we assessed developmental relationships between thymic dendritic cells and thymocytes, employing retrovirus-based cellular barcoding and reporter mice, as well as intrathymic transfers coupled with DC depletion. We demonstrated that a subset of early T-lineage progenitors expressed CX3CR1, a bona fide marker for DC progenitors. However, intrathymic transfers into nonmanipulated mice, as well as retroviral barcoding, indicated that thymic dendritic cells and thymocytes were largely of distinct developmental origin. In contrast, intrathymic transfers after in vivo depletion of DCs resulted in intrathymic development of non-T-lineage cells. In conclusion, our data support a model in which the adoption of T-lineage fate by noncommitted progenitors at steady state is enforced by signals from the thymic microenvironment unless niches promoting alternative lineage fates become available. (Blood. 2015;125(3):457-464)

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“…MyrAkt2 Tg were generated as previously described using a proximal Lck promoter to restrict expression to T lineage progenitors (18). Conditional ablation of the Pten locus in T lineage progenitors was accomplished by crossing Pten flox/flox mice (19) with those expressing Cre in T lineage progenitors only, under control of the pre-Tα promoter (14). Upon crossing MyrAkt2 Tg or PTEN-deficient mice to Rpl22 −/− mice, littermates on a mixed 129-C57BL/6 background were monitored weekly for signs of disease, as described (2).…”

Section: Methodsmentioning

confidence: 99%

“…Indeed, Gutierrez et al reported alterations of the PTEN-PI3K-Akt pathway in nearly 50% of pediatric T-ALL (12). The two models used were a MyrAkt2 Tg mouse, in which MyrAkt2 is expressed in T lineage progenitors under the control of a proximal Lck promoter (13) and a conditional knockout mouse where the Pten tumor suppressor gene is ablated in T cell precursors using pre-Tα-Cre (14). Interestingly, both enforced expression of MyrAkt2 and biallelic loss of Pten resulted in a partial rescue of the block in T cell development caused by Rpl22-deficiency.…”

Section: Introductionmentioning

confidence: 99%

Ribosomal Protein Rpl22 Controls the Dissemination of T-cell Lymphoma

et al. 2016

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Mutations in ribosomal proteins cause bone marrow failure syndromes associated with increased cancer risk, but the basis by which they do so remains unclear. We reported previously that the ribosomal protein Rpl22 is a tumor suppressor in T cell acute lymphoblastic leukemia/lymphoma (T-ALL), and that loss of just one Rpl22 allele accelerates T-cell lymphomagenesis by activating NF-κB and inducing the stem cell factor Lin28B. Here, we show that, paradoxically, loss of both alleles of Rpl22 restricts lymphoma progression through a distinct effect on migration of malignant cells out of the thymus. Lymphoma-prone AKT2-transgenic or PTEN-deficient mice on an Rpl22−/− background developed significantly larger and markedly more vascularized thymic tumors than those observed in Rpl22+/+ control mice. But, unlike Rpl22+/+ or Rpl22+/− tumors, Rpl22−/− lymphomas did not disseminate to the periphery and were retained in the thymus. We traced the defect in the Rpl22−/− lymphoma migratory capacity to downregulation of the KLF2 transcription factor and its targets, including the key migratory factor sphingosine 1-phosphate receptor 1 (S1PR1). Indeed, re-expression of the S1PR1 in Rpl22-deficient tumor cells restores their migratory capacity in vitro. The regulation of KLF2 and S1PR1 by Rpl22 appears to be proximal as Rpl22 re-expression in Rpl22-deficient lymphoma cells restores expression of KLF2 and S1P1R, while Rpl22 knockdown in Rpl22-sufficient lymphomas attenuates their expression. Collectively, these data reveal that, while loss of one copy of Rpl22 promotes lymphomagenesis and disseminated disease, loss of both copies impairs responsiveness to migratory cues and restricts malignant cells to the thymus.

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In vivo fate mapping identifies pre-TCRα expression as an intra- and extrathymic, but not prethymic, marker of T lymphopoiesis

Abstract: A novel pre-TCRα (pTα) reporter mouse reveals that expression of pTα is confined to the T lineage and does not occur on prethymic progenitors.

Cited by 22 publications

References 67 publications

Noncanonical Mode of ERK Action Controls Alternative αβ and γδ T Cell Lineage Fates

Noncanonical Mode of ERK Action Controls Alternative αβ and γδ T Cell Lineage Fates

Limited niche availability suppresses murine intrathymic dendritic-cell development from noncommitted progenitors

Ribosomal Protein Rpl22 Controls the Dissemination of T-cell Lymphoma

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