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

Bhandoola, Avinash; Boehmer, Harald von; Petrie, Howard T.; Zúñiga‐Pflücker, Juan Carlos

doi:10.1016/j.immuni.2007.05.009

Cited by 243 publications

(237 citation statements)

References 104 publications

(179 reference statements)

Supporting

Mentioning

228

Contrasting

Order By: Relevance

“…15,16 The identification of a putative LMPP, representing the earliest lineage-restricted lympho-myeloid progenitor identified in adult hematopoiesis, has provided a potential avenue toward uncovering alternative HSC lineage commitment pathways. 2,3,17 However, the existence of the LMPP remains contentious, 2,3,[18][19][20] largely reflecting functional heterogeneity of phenotypically defined candidate LMPPs. 9,10,[12][13][14] While the evidence for a large fraction of LSKFlt3 hi BM cells sustaining (at the single cell level) combined and robust GM and lymphoid potentials are compelling, 9,10,14,15 the experimental evidence for LMPPs having lost MkE potential has been questioned.…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential

Luc

Anderson

Kharazi

et al. 2008

Blood

View full text Add to dashboard Cite

IntroductionWhereas considerable knowledge has been gained with regard to the identity and roles of extrinsic and intrinsic regulators of blood lineage development, much less is known about the molecular mechanisms regulating lineage commitment of hematopoietic stem cells (HSCs). 1,2 Unraveling the involved molecular determinants and mechanisms of lineage restriction will be facilitated by, and most likely depend on, a more complete understanding of the cellular pathways of the lineage restriction process from pluripotent HSCs to lineage-restricted progenitor cells.It remains unclear and debated 2-4 exactly how the lineage commitment process from pluripotent HSCs to lineage-restricted progenitors occurs in adult bone marrow (BM), and even unequivocal evidence for one such pathway would not exclude the existence of alternative routes for HSC lineage commitment. In the prevailing model of HSC lineage commitment, 1-3 HSCs (long-term and short-term) and multipotent progenitors (MPPs) distinguish themselves from each other, only through gradual loss of self-renewal potential while sustaining the same degree of pluripotentiality, with the first lineage commitment event resulting in a strict separation of myelopoiesis and lymphopoiesis. This model for HSC lineage commitment was supported by the identification of common myeloid and common lymphoid progenitors (CMPs and CLPs, respectively). 5,6 However, the degree to which the identified CMPs and CLPs represent obligatory or even main intermediates for myeloid and lymphoid development in adult hematopoiesis remains to be established.Although conclusively established for long-term HSCs (LTHSCs), 7,8 the existence of short-term HSCs (ST-HSCs) and MPPs in the BM Lin Ϫ Sca-1 ϩ Kit ϩ (LSK) stem and primitive progenitor cell compartment, with sustained pluripotentiality has yet to be demonstrated at the single cell level. 3 Rather, more recent studies have uncovered considerable heterogeneity in the LSK MPP compartment. Through the use of different but overlapping markers such as FMS-like tyrosine kinase 3 (Flt3), 9-11 vascular cell adhesion molecule-1 (Vcam-1), 12,13 and an Ikaros-reporter, 14 the existence of lymphoid-primed MPPs (LMPPs) with combined granulocyte/monocyte (GM) and lymphoid potentials, but little or no megakaryocyte (Mk)/erythroid (E) potentials has been proposed. 3,10,12,14,15 Further, molecular analysis of putative LMPPs show down-regulated transcriptional priming of genes specific for the MkE lineage, and up-regulation of lymphoid-specific genes, not yet expressed in HSCs. 15,16 The identification of a putative LMPP, representing the earliest lineage-restricted lympho-myeloid progenitor identified in adult hematopoiesis, has provided a potential avenue toward uncovering alternative HSC lineage commitment pathways. 2,3,17 However, the existence of the LMPP remains contentious, 2,3,[18][19][20] largely reflecting functional heterogeneity of phenotypically defined candidate LMPPs. 9,10,[12][13][14] While the evidence for a large fraction of LSKFlt3 hi BM cell...

show abstract

Section: Introductionmentioning

confidence: 99%

Down-regulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential

Luc

Anderson

Kharazi

et al. 2008

Blood

View full text Add to dashboard Cite

show abstract

“…26 The assembly and expression of functional Tcrb genes in CD25 ¡ CD117 C CD4 ¡ CD8 ¡ (DN3) thymocytes activates signals that promote differentiation of these cells into CD25 ¡ CD117 ¡ CD4 ¡ CD8 ¡ (DN4) thymocytes and then into CD4 C CD8 C (DP) thymocytes. 27 Tcrb expression in DN3 cells also activates Cyclin D3 expression to drive proliferation and expansion as these cells develop into DP thymocytes. 7 Following arrest in G1 phase, DP thymocytes can further differentiate without proliferation into CD4 C or CD8 C (SP) thymocytes, which exit the thymus as quiescent mature ab T cells.…”

Section: Dsbs Signal Atm-dependent Repression Of Cyclin D3 Protein Lementioning

confidence: 99%

“…7 Following arrest in G1 phase, DP thymocytes can further differentiate without proliferation into CD4 C or CD8 C (SP) thymocytes, which exit the thymus as quiescent mature ab T cells. 27 We performed cell counting and flow cytometry analyses for T cell markers on thymocytes and splenocytes of 4 to 6 weeks old LckCre C HuR flox/flox (HuRD/D) and littermate HuR flox/flox (HuRf/f) mice. Compared to HuRf/f mice, HuRD/D mice have »3-fold and »4.5-fold lower numbers of total thymocytes and splenic ab T cells, respectively (Fig.…”

Section: Dsbs Signal Atm-dependent Repression Of Cyclin D3 Protein Lementioning

confidence: 99%

Lymphocyte lineage-specific and developmental stage specific mechanisms suppress cyclin D3 expression in response to DNA double strand breaks

et al. 2016

View full text Add to dashboard Cite

Mammalian cells are thought to protect themselves and their host organisms from DNA double strand breaks (DSBs) through universal mechanisms that restrain cellular proliferation until DNA is repaired. The Cyclin D3 protein drives G1-to-S cell cycle progression and is required for proliferation of immature T and B cells and of mature B cells during a T cell-dependent immune response. We demonstrate that mouse thymocytes and pre-B cells, but not mature B cells, repress Cyclin D3 protein levels in response to DSBs. This response requires the ATM protein kinase that is activated by DSBs. Cyclin D3 protein loss in thymocytes coincides with decreased association of Cyclin D3 mRNA with the HuR RNA binding protein that ATM regulates. HuR inactivation reduces basal Cyclin D3 protein levels without affecting Cyclin D3 mRNA levels, indicating that thymocytes repress Cyclin D3 expression via ATM-dependent inhibition of Cyclin D3 mRNA translation. In contrast, ATM-dependent transcriptional repression of the Cyclin D3 gene represses Cyclin D3 protein levels in pre-B cells. Retrovirus-driven Cyclin D3 expression is resistant to transcriptional repression by DSBs; this prevents pre-B cells from suppressing Cyclin D3 protein levels and from inhibiting DNA synthesis to the normal extent following DSBs. Our data indicate that immature B and T cells use lymphocyte lineage-and developmental stage-specific mechanisms to inhibit Cyclin D3 protein levels and thereby help prevent cellular proliferation in response to DSBs. We discuss the relevance of these cellular context-dependent DSB response mechanisms in restraining proliferation, maintaining genomic integrity, and suppressing malignant transformation of lymphocytes.

show abstract

“…The V(D)J recombination process is also influenced by general DSB response factors such as the ataxia telangiec tasia mutated (ATM) protein (Liyanage et al, 2000;Bredemeyer et al, 2006;Callén et al, 2007;Huang et al, 2007). In humans and mice, the two distinct lineages of T lymphocytes are dis tinguished by the surface expression of either  or  TCRs (Bhandoola et al, 2007). TCR, , and  variable region exons are assembled in CD4  /CD8  (double negative) thy mocytes (von Boehmer, 2004).…”

Section: Recurrent Amplification Upstream Of Tcra/d Locus In Atm-defimentioning

confidence: 99%

ATM-deficient thymic lymphoma is associated with aberranttcrdrearrangement and gene amplification

Zha¹,

Bassing²,

Sanda³

et al. 2010

J Cell Biol

View full text Add to dashboard Cite

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

Cited by 243 publications

References 104 publications

Down-regulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential

Down-regulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential

Lymphocyte lineage-specific and developmental stage specific mechanisms suppress cyclin D3 expression in response to DNA double strand breaks

ATM-deficient thymic lymphoma is associated with aberranttcrdrearrangement and gene amplification

Contact Info

Product

Resources

About