The B lineage potential of thymus settling progenitors is critically dependent on mouse age

Ceredig, Rhodri; Bosco, Nabil; Rolink, Antonius

doi:10.1002/eji.200636728

Cited by 28 publications

(30 citation statements)

References 35 publications

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“…It is important to note that our conclusions apply only to adult mice. The frequency of ETPs with B-lineage potential is increased in neonatal mice, 13,45 and ETPs may be a more significant source of thymic B cells in early life.…”

Section: Discussionmentioning

confidence: 98%

Early T-cell progenitors are the major granulocyte precursors in the adult mouse thymus

Obaldia

Bell

Bhandoola

2013

Blood

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Key Points• Granulocytes in the adult mouse thymus share a common origin with T cells, because they derive from ETPs.• The finding that ETPs generate myeloid cells in vivo indicates that precursors settling the thymus include myelolymphoid progenitors. IntroductionSince the identification of early T-lineage precursors (ETPs), 1 much work has characterized the developmental potentials possessed by this population. [2][3][4][5][6][7][8][9][10][11][12][13] In addition to robust T-cell developmental potential, ETPs have been shown to possess B cell, dendritic cell (DC), and natural killer (NK) cell potential and a degree of myeloid potential. As ETPs progress along the T-cell developmental pathway, they gradually lose non-T-cell potentials and generate CD4/ CD8-double negative 2 (DN2) progenitors and, finally, DN3 cells that are committed to the T-cell lineage. Single-cell assays using a stromal cell culture system have shown that the majority of individual ETPs can give rise to both T cells and myeloid cells, including granulocytes and macrophages. 10,11 However, less is known about the extent to which ETPs realize this myeloid potential and other non-T-cell lineage potentials in vivo. We reported previously that approximately half of ETPs and a similar fraction of thymic granulocytes were labeled in H2-VEX V(D)J recombination reporter mice. 10 These data are consistent with the notion that thymic granulocytes share a common origin with T cells. Since then, another study examining thymic myeloid cells using an IL-7 receptor (IL-7R)/Cre lineage tracing approach yielded discordant results. 12 Therefore, further examination was needed to determine whether ETPs can produce granulocytes in vivo and whether ETPs are the major precursors of thymic granulocytes. An understanding of whether ETPs generate both myeloid and T-cell progeny in vivo will contribute to a more complete model of hematopoietic development.In the present study, we examined thymic granulocyte development in experimental contexts in which ETPs are nearly absent. We reasoned that non-T-lineage cells in the thymus that are unperturbed in the absence of ETPs in mixed-BM chimeras must not predominantly derive from ETPs. Previous studies used a similar approach to investigate whether non-T-lineage cells in the thymus originate from T-cell progenitors; however, these studies did not examine thymic granulocytes. 14,15 Studies using models that exclusively block intrathymic ETP development (eg, by ablating Notch signaling) may fail to detect a common origin with T-cell progenitors because progenitors continue to settle the thymus and may still generate non-T-lineage cells even when ETP development is abrogated. To address this concern, we chose to study the development of non-T-lineage cells in the thymus by eliminating T-cell progenitors before thymic entry. Specifically, we examined mixed chimeras using CCR7/CCR9 double-deficient donor BM in which T-cell progenitors display defective thymic settling and thus generate almost no ETPs. In addition, we examined ...

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Section: Discussionmentioning

confidence: 98%

Early T-cell progenitors are the major granulocyte precursors in the adult mouse thymus

Obaldia

Bell

Bhandoola

2013

Blood

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“…However, these T-B potent ETPs are estimated to be a very small fraction of the ETP population (Porritt et al, 2004;Balciunaite et al, 2005;Lu et al, 2005;Sambandam et al, 2005;Ceredig et al, 2007). A key prediction of this model, therefore, is that thymus-settling ELPs undergo extensive cell division, generating large numbers of downstream ETPs.…”

Section: Is the Thymus Colonized By Lymphoid-specified Progenitors Wimentioning

confidence: 96%

“…Progenitor populations defined as DN1 Kit hi , or as ETP, are themselves heterogeneous, and subsets have been described with CD24 (Porritt et al, 2004), Flt3 (CD135) (Sambandam et al, 2005), and CCR9-EGFP expression in CCR9 reporter mice (Benz and Bleul, 2005;Heinzel et al, 2007). The rare ETP subset defined by expression of Flt3, and also by expression of high levels of EGFP in CCR9 reporter mice, contains some B lineage potential (Benz and Bleul, 2005;Sambandam et al, 2005;Ceredig et al, 2007;Heinzel et al, 2007). For some ETPs, T and B potential have been demonstrated in the same cell (Benz and Bleul, 2005;Heinzel et al, 2007).…”

Section: Progenitors In Thymusmentioning

confidence: 98%

Commitment and Developmental Potential of Extrathymic and Intrathymic T Cell Precursors: Plenty to Choose from

et al. 2007

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T cells developing in the thymus are derived from hematopoietic stem cells (HSCs) in the bone marrow (BM). Understanding the developmental steps linking multipotent HSCs to intrathymic T lineage-committed progenitors is important for understanding cancer in T lineage cells, improving T cell reconstitution after BM transplantation, and designing gene-therapy approaches to treat defective T cell development or function. Such an understanding may also help ameliorate immunological defects in aging. This review covers the differentiation steps between HSCs and committed T cell progenitors within the thymus.

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“…It is generally believed that the so-called thymic seeding precursor (TSP) still has the capability of generating B cells, NK cells, DCs and other myeloid cells [2,5,6,10,11]. Upon receiving the Notch signal, the differentiation potential towards the B-cell lineage of the TSP is rapidly lost [2,10,11], whereas other lineage options are still maintained [2,5,6,10,11]. However, a recent study using an IL-7Ra reporter mouse indicated that the non-T-cell lineage differentiation of these progenitors is not, or only very rarely, occurring under physiologic conditions [12,13].…”

Section: Introductionmentioning

confidence: 99%

The preTCR‐dependent DN3 to DP transition requires Notch signaling, is improved by CXCL12 signaling and is inhibited by IL‐7 signaling

et al. 2011

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The requirement for Notch signaling during T-cell development has been extensively studied. Nevertheless, the developmental stage at which it is required and whether additional signaling pathways are needed are still poorly understood. By using a stromalcell-free culture system, we show that sorted double-negative 3 (DN3) thymocytes only require a Delta-like-4-induced Notch signal to differentiate into double-positive (DP) cells. This differentiation process is preTCR-a dependent. DN3 cells undergo 4-5 proliferation cycles, and the addition of the chemokine CXCL12 improves proliferation. IL-7 blocks the differentiation of DN3 cells to DP cells but not the Notch-induced proliferation of cultured DN3 cells. The impaired differentiation correlates with an inhibition of Rag-2 upregulation. Overall, the in vitro stromal-cell-free culture system presented here also provides a powerful and unique tool for studying the mechanisms involved in the positive and negative selection of T cells.Key words: Delta-like 4 and preTCR . DN3 cells . Double-positive cells . Notch IntroductionTo maintain T lymphopoiesis, progenitor cells from the BM constantly seed the thymus. In transplantation settings, it has been shown that different progenitors can home to the thymus and generate T cells [1][2][3][4][5][6][7][8][9]. However, under physiological conditions the role of each of these progenitors is still unclear. It is generally believed that the so-called thymic seeding precursor (TSP) still has the capability of generating B cells, NK cells, DCs and other myeloid cells [2,5,6,10,11]. Upon receiving the Notch signal, the differentiation potential towards the B-cell lineage of the TSP is rapidly lost [2,10,11], whereas other lineage options are still maintained [2,5,6,10,11]. However, a recent study using an IL-7Ra reporter mouse indicated that the non-T-cell lineage differentiation of these progenitors is not, or only very rarely, occurring under physiologic conditions [12,13].Within the thymus, the earliest thymocytes are characterized by the absence of CD4 and CD8 expression and are therefore called double-negative (DN) cells. Based on the expression of CD25, CD44 and CD117, DN cells can be subdivided into four subpopulations. DN1 cells express high cell surface levels of CD44 and CD117, and are negative for CD25, whereas their DN2 progeny express all three markers [14][15][16]. In vitro, DN1 and DN2 cells still possess the capacity to differentiate into NK cells, DCs and other myeloid cells [5,6,11,17] suggesting that they are not yet restricted to the T-cell lineage. T-cell commitment is achieved at the DN3 stage. However, the mechanisms operating . It is at this stage of development that the rearrangement of the TCR-b chain locus is completed, and the cells are selected for a productive TCR-b chain rearrangement, also known as the b-selection checkpoint [18][19][20]. DN3 cells that have rearranged their TCR-b chain locus unproductively can either differentiate into g/d T cells or will otherwise undergo apoptosis. DN3 cells car...

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The B lineage potential of thymus settling progenitors is critically dependent on mouse age

Cited by 28 publications

References 35 publications

Early T-cell progenitors are the major granulocyte precursors in the adult mouse thymus

Early T-cell progenitors are the major granulocyte precursors in the adult mouse thymus

Commitment and Developmental Potential of Extrathymic and Intrathymic T Cell Precursors: Plenty to Choose from

The preTCR‐dependent DN3 to DP transition requires Notch signaling, is improved by CXCL12 signaling and is inhibited by IL‐7 signaling

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