Transcriptional priming of intrathymic precursors for dendritic cell development

Moore, Amanda J.; Sarmiento, Janice; Mohtashami, Mahmood; Braunstein, Marsela; Zúñiga-Pflücker, Juan-Carlos; Anderson, Michele K.

doi:10.1242/dev.069344

Cited by 20 publications

(42 citation statements)

References 62 publications

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“…In agreement with our results, elegant work from Benz et al (39) clearly shows that newly arriving progenitors that reach the thymus differentiate through the ETP stage of development early after arrival and do not adopt the DN1c, DN1d, and DN1e lineages with the same kinetics. Furthermore, work from several groups has illustrated that the DN1c, DN1d, and DN1e populations are not significant progenitors of T cells, but rather give rise to other lineages of cells (40,41). These results, along with our data, suggest that the development of DN1c, DN1d, and DN1e cells is temporally distinct from that of ETPs and likely occurs downstream of ETP generation or through progenitor populations distinct from those that form the ETP pool and give rise to T cells.…”

Section: Discussionsupporting

confidence: 64%

RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors

Golec

Caviedes

Baldwin

2016

The Journal of Immunology

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T cell development is dependent on the migration of progenitor cells from the bone marrow to the thymus. Upon reaching the thymus, progenitors undergo a complex developmental program that requires inputs from various highly conserved signaling pathways including the Notch and Wnt pathways. To date, Ras signaling has not been implicated in the very earliest stages of T cell differentiation, but members of a family of Ras activators called RasGRPs have been shown to be involved at multiple stages of T cell development. We examined early T cell development in mice lacking RasGRP1, RasGRP3, and RasGRPs 1 and 3. We report that RasGRP1- and RasGRP3-deficient thymi show significantly reduced numbers of early thymic progenitors (ETPs) relative to wild type thymi. Furthermore, RasGRP1/3 double-deficient thymi show significant reductions in ETP numbers compared with either RasGRP1 or RasGRP3 single-deficient thymi, suggesting that both RasGRP1 and RasGRP3 regulate the generation of ETPs. In addition, competitive bone marrow chimera experiments reveal that RasGRP1/3 double-deficient progenitors intrinsically generate ETPs less efficiently than wild type progenitors. Finally, RasGRP1/3-deficient progenitors show impaired migration toward the CCR9 ligand, CCL25, suggesting that RasGRP1 and RasGRP3 may regulate progenitor entry into the thymus through a CCR9-dependent mechanism. These data demonstrate that, in addition to Notch and Wnt, the highly conserved Ras pathway is critical for the earliest stages of T cell development and further highlight the importance of Ras signaling during thymocyte maturation.

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Section: Discussionsupporting

confidence: 64%

RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors

Golec

Caviedes

Baldwin

2016

The Journal of Immunology

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“…3,46 Specifically, CD8␣ ϩ thymic cDCs have been proposed to originate from ETPs. 47,48 We found that thymic cDC subsets are unlabeled in RAG-1/Cre reporter mice, which is consistent with previous reports that this population lacks TCR rearrangements.…”

Section: Discussionmentioning

confidence: 99%

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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“…Previous studies have demonstrated dendritic cell potential of DN1d and DN1e subsets in vivo (41) and the ability of IL-18 to drive differentiation of fetal DN1 cells to dendritic cells (22). However, in our OP9-DL4 co-cultures, IL-18- induced proliferative effects appeared restricted to DN1a/b (ETP) and DN2 cells that progressed toward DN3 as we observed no expansion of the of DN1d/e cells in this system (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

IL-18 Acts in Synergy with IL-7 To Promote Ex Vivo Expansion of T Lymphoid Progenitor Cells

Gandhapudi

Tan

Marino

et al. 2015

The Journal of Immunology

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Although IL-18 has not previously been shown to promote T lymphopoiesis, results obtained via a novel data mining algorithm (GAMMA), led us to explore a predicted role for this cytokine in T cell development. IL-18 is a member of the IL-1 cytokine family that has been extensively characterized as a mediator of inflammatory immune responses. To assess a potential role for IL-18 in T cell development, we sort-purified mouse bone marrow derived common lymphoid progenitor cells (CLP), early thymic progenitors (ETP) and DN2 thymocytes and cultured these populations on OP9-DL4 stromal layers in the presence or absence of IL-18 and/or IL-7. After one week of culture, IL-18 promoted proliferation and accelerated differentiation of ETPs to the DN3 stage, similar in efficiency to IL-7. IL-18 showed synergy with IL-7 and enhanced proliferation of both the thymus derived progenitor cells and the bone marrow derived common lymphoid progenitor cells. The synergistic effect on the ETP population was further characterized and found to correlate with increased surface expression of c-Kit and IL-7 receptors on the IL-18-treated cells. In summary, we successfully validated the GAMMA prediction that IL-18 affects T lymphopoiesis and demonstrated that IL-18 can positively impact bone marrow lymphopoiesis and T cell development, presumably via interaction with the c-Kit and IL-7 signaling axis.

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Transcriptional priming of intrathymic precursors for dendritic cell development

Abstract: There was an error published in Development 139, 373-384.In the legend to Fig. 10, the authors incorrectly stated that donor cells were injected intrathymically rather than intravenously. The correct figure legend appears below. The authors apologise to readers for this mistake.

Cited by 20 publications

References 62 publications

RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors

RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors

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

IL-18 Acts in Synergy with IL-7 To Promote Ex Vivo Expansion of T Lymphoid Progenitor Cells

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