The Blood Contains Multiple Distinct Progenitor Populations with Clonogenic B and T Lineage Potential

Umland, Oliver; Mwangi, William; Anderson, Bradley M.; Walker, Juliette C.; Petrie, Howard T.

doi:10.4049/jimmunol.178.7.4147

Cited by 19 publications

(19 citation statements)

References 28 publications

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“…Our phenotypic analysis of blood-derived precursor populations is in agreement with previous work, indicating that most BM-derived T-cell precursors such as MPPs and CLPs as well as CLP-like cells have been found in blood. 27 However, CLP-2 cells remain yet to be identified above the limit of detection and a direct BM-resident precursor of CTPs remains elusive. 11 Comparison of phenotypically matched precursors in BM and blood revealed virtually no differences with respect to lineage potential and differentiation kinetics.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Umland et al identified a CD127 Ϫ/lo population with otherwise CLP-like characteristics that would not be included in our depletion approach and may constitute a physiologic T-lineage precursor. 27 To reach the thymus, precursors must enter the circulation. Our study revealed that in both BM and blood multiple progenitor populations capable of thymus seeding and T-lineage reconstitution exist.…”

Section: Discussionmentioning

confidence: 99%

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Multiple extrathymic precursors contribute to T-cell development with different kinetics

Saran

Łyszkiewicz

Pommerencke

et al. 2010

Blood

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T-cell development in the thymus depends on continuous supply of T-cell progenitors from bone marrow (BM). Several extrathymic candidate progenitors have been described that range from multipotent cells to lymphoid cell committed progenitors and even largely T-lineage committed precursors. However, the nature of precursors seeding the thymus under physiologic conditions has remained largely elusive and it is not known whether there is only one physiologic T-cell precursor population or many. Here, we used a competitive in vivo assay based on depletion rather than enrichment of classes of BM-derived precursor populations, thereby only minimally altering physiologic precursor ratios to assess the contribution of various extrathymic precursors to T-lineage differentiation. We found that under these conditions multiple precursors, belonging to both multipotent progenitor (MPP) and common lymphoid progenitor (CLP) subsets have robust T-lineage potential. However, differentiation kinetics of different precursors varied considerably, which might ensure continuous thymic output despite gated importation of extrathymic precursors. In conclusion, our data suggest that the thymus functions to impose T-cell fate on any precursor capable of filling the limited number of progenitor niches. (Blood. 2010;115:1137-1144) IntroductionT-cell development in the thymus depends on continuous supply of T-cell progenitors from bone marrow (BM) via the circulation. In the thymus T-cell precursors pass through a series of defined developmental stages, with the most immature thymocytes residing in the double-negative (DN) subset, characterized by the absence of the surface markers CD4 and CD8. Thymocyte differentiation then proceeds through the CD4 ϩ CD8 ϩ double-positive (DP) stage, after which thymocytes become either CD4 or CD8 single positive (SP) and leave the thymus to enter the mature T-cell pool. The most immature T-cell progenitors in the thymus are lineage negative (lin Ϫ ), CD44 ϩ , CD25 Ϫ , Sca-1 high , CD117 (c-kit) high (LSK), and CD127 Ϫ/lo (IL-7R␣) early T-lineage progenitors (ETPs), 1 which constitute a subfraction of the CD44 ϩ CD25 Ϫ DN1 population. These cells were shown to have high T but only limited B and some myeloid potential. 2,3 ETPs could be further subdivided according to their expression levels of CD135 (Fms-like tyrosine kinase receptor 3 [Flt3]) 4 and loss of CD135 expression correlated with loss of B-cell potential.Like all hematopoietic lineages T cells are ultimately derived from hematopoietic stem cells (HSCs) residing in BM. HSCs can generate CD135 ϩ multipotent progenitors (MPPs), which are likewise of the LSK phenotype, 5 as well as more committed precursors such as RAG-1-positive early lymphoid progenitors (ELPs) 6 and L-selectin-positive progenitors (LSPs), 7 both of which constitute subsets of MPPs. Common lymphoid progenitors (CLPs), 8 which are lin Ϫ Sca-1 ϩ CD117 ϩ/lo CD127 ϩ CD135 ϩ , and lin Ϫ Sca-1 ϩ CD117 Ϫ CD127 ϩ CD135 ϩ B220 ϩ CLP-2 9 differ from MPP subsets in their lack of myeloid pot...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Multiple extrathymic precursors contribute to T-cell development with different kinetics

Saran

Łyszkiewicz

Pommerencke

et al. 2010

Blood

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“…The LMPP, the ELP and the CLP are detectable in peripheral blood, whereas the CLP-2 has not been found in the blood (Schwarz and Bhandoola, 2004;Perry et al, 2006;Krueger and von Boehmer, 2007;Umland et al, 2007). Recently, a novel T-lineage-committed progenitor subset presumably downstream of the CLP-2 was found in adult murine blood.…”

Section: Developmental Pathways In Murine Hematopoiesismentioning

confidence: 99%

Hematopoietic developmental pathways: on cellular basis

Iwasaki

Akashi

2007

Oncogene

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“…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.…”

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 Blood Contains Multiple Distinct Progenitor Populations with Clonogenic B and T Lineage Potential

Cited by 19 publications

References 28 publications

Multiple extrathymic precursors contribute to T-cell development with different kinetics

Multiple extrathymic precursors contribute to T-cell development with different kinetics

Hematopoietic developmental pathways: on cellular basis

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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