In-frame TCR δ gene rearrangements play a critical role in the αβ/γδ T cell lineage decision

The earliest steps of intrathymic differentiation recently have been elucidated. It has been reported that both CD4lo (CD44+ CD25- c-kit+ CD3- CD4lo CD8-) and pro-T cells (CD44+ CD25+ c-kit+ CD3- CD4- CD8-, representing the next step in maturation) exhibit germline T-cell receptor beta and gamma loci, suggesting that neither population is exclusively committed to the T-cell lineage. Several groups have shown that CD4lo cells retain the capacity to generate multiple lymphoid lineages in vivo; however, the lineage commitment status of pro-T cells is unknown. To determine when T-cell lineage commitment occurs, we examined the ability of sorted CD4lo and pro-T cells to generate lymphoid lineage cells in vivo or in fetal thymic organ cultures (FTOCs). When intravenously injected into scid mice, CD4lo cells generated both T and B cells, whereas the progeny of pro-T cells contained T cells exclusively. Fetal thymic organ cultures repopulated with CD4lo cells contained both T and natural killer (NK) cells, whereas cultures repopulated with pro-T cells contained T cells almost exclusively. These observations strongly suggest that T-cell lineage commitment occurs during the transition of CD4lo to pro-T cells. Because it is likely that the thymic microenvironment plays a critical role in T-cell commitment, we compared the responses of CD4lo and pro-T cells to various cytokine combinations in vitro, as well as the ability of the cultured cells to repopulate organ cultures. Cytokine combinations that maintained T-cell repopulation potential for both CD4lo and pro-T cells were found. CD4lo cells proliferated best in response to the combination containing interleukin-1 (IL-1), IL-3, IL- 6, IL-7, and stem cell factor (SCF). Unlike CD4lo cells, pro-T cells were much more dependent upon IL-7 for proliferation and FTOC repopulation. However, combinations of cytokines lacking IL-7 were found that maintained the T-cell repopulating potential of pro-T cells, suggesting that, whereas this cytokine is clearly very important for normal pro-T cell function, it is not an absolute necessity during early T-cell expansion and differentiation.

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A new family of markers to characterize the human γδ T-cell lineage

10.31219/osf.io/jzcf3 ◽

2019 ◽

Author(s):

Shahan Mamoor

Keyword(s):

T Cells ◽

T Cell ◽

Differentially Expressed Genes ◽

Cell Lineage ◽

Γδ T Cells ◽

Differentially Expressed ◽

Γδ T Cell ◽

Differentiation Markers ◽

Hematopoietic Stem ◽

New Family

Prospective isolation of γδ T lymphocytes demands a comprehensive description of the molecules that distinguish T cells with γδ T-cell receptors (TCRs) (γδ T cells, or Tγδ) from those with αβTCRs (Tαβ). Here I describe some of the most differentially expressed genes in the γδ T cell when compared to the developmentally proximal but lineage-distinct Tαβ CD4+ and CD8+ lymphocytes. These genes encode cluster of differentiation markers, transcription factors, cell surface receptors and non-coding RNAs. As hematopoietic stem cells (HSCs) have been prospectively isolated based on the analysis of differentially expressed genes (1), any combination of these molecules may potentially be used to isolate Tγδ, perhaps even independent of the γδTCR. This description of the most striking identifying features of the Tγδ will be a resource for the isolation of a multi-potent common γδ T-cell progenitor.

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Delta-like1-induced Notch1 signaling regulates the human plasmacytoid dendritic cell versus T-cell lineage decision through control of GATA-3 and Spi-B

Blood ◽

10.1182/blood-2005-05-2090 ◽

2006 ◽

Vol 107 (6) ◽

pp. 2446-2452 ◽

Cited By ~ 70

Author(s):

Wendy Dontje ◽

Remko Schotte ◽

Tom Cupedo ◽

Maho Nagasawa ◽

Ferenc Scheeren ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Plasmacytoid Dendritic Cell ◽

Ectopic Expression ◽

Cell Lineage ◽

Notch1 Signaling ◽

Lineage Decision ◽

Multiple Cell ◽

Ets Family ◽

Notch1 Signaling Pathway

AbstractHuman early thymic precursors have the potential to differentiate into multiple cell lineages, including T cells and plasmacytoid dendritic cells (pDCs). This decision is guided by the induction or silencing of lineage-specific transcription factors. The ETS family member Spi-B is a key regulator of pDC development, whereas T-cell development is critically dependent on GATA-3. Here we show that triggering of the Notch1 signaling pathway by Delta-like1 controls the T/pDC lineage decision by regulating the balance between these factors. CD34+CD1a- thymic progenitor cells express Notch1, but down-regulate this receptor when differentiating into pDCs. On coculture with stromal cell lines expressing either human Delta-like1 (DL1) or Jagged1 (Jag1) Notch ligands, thymic precursors express GATA-3 and develop into CD4+CD8+TCRαβ+ T cells. On the other hand, DL1, but not Jag1, down-regulates Spi-B expression, resulting in impaired development of pDCs. The Notch1-induced block in pDC development can be relieved through the ectopic expression of Spi-B. These data indicate that DL1-induced activation of the Notch1 pathway controls the lineage commitment of early thymic precursors by altering the levels between Spi-B and GATA-3. (Blood. 2006;107:2446-2452)

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Interleukin 3 (IL-3) induces transcription from nonrearranged T cell receptor gamma loci in IL-3-dependent cell lines.

Journal of Experimental Medicine ◽

10.1084/jem.169.6.2059 ◽

1989 ◽

Vol 169 (6) ◽

pp. 2059-2071 ◽

Cited By ~ 20

Author(s):

Y Weinstein ◽

K Morishita ◽

J L Cleveland ◽

J N Ihle

Keyword(s):

T Cell ◽

Growth Factor ◽

T Cell Receptor ◽

Cell Lines ◽

Cell Lineage ◽

Cell Receptor ◽

Cdna Clones ◽

Gene Rearrangements ◽

Interleukin 3 ◽

Dependent Cell

The expression of the murine TCR-gamma genes was examined in a series of IL-3-dependent and growth factor-independent cell lines. All of the IL-3-dependent cell lines, but none of the IL-3-independent lines, expressed high levels of one or more of the gamma genes but did not express the TCR-beta genes. None of the cell lines expressing the gamma loci contained detectable genomic gamma gene rearrangements. Sequencing of cDNA clones from two of the cell lines demonstrated that transcription was from nonrearranged gamma loci based on the presence of sequences in the cDNAs that are found immediately 5' of the J gamma 4 and J gamma 2 genes. The expression of gamma transcripts was dependent upon IL-3 and no transcripts were detectable within 6-8 h after the removal of IL-3. Readdition of IL-3, but not granulocyte CSF, resulted in the reappearance of gamma transcripts within 30 min. The results demonstrate that IL-3 regulates the expression of nonrearranged gamma loci. Since expression is required for rearrangement, it can be hypothesized that IL-3 may influence the ability of lymphoid/myeloid progenitors to commit to the T cell lineage.

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CD94 1A transcripts characterize lymphoblastic lymphoma/leukemia of immature natural killer cell origin with distinct clinical features

Blood ◽

10.1182/blood-2005-02-0519 ◽

2005 ◽

Vol 106 (10) ◽

pp. 3567-3574 ◽

Cited By ~ 15

Author(s):

Chung-Wu Lin ◽

Ting-Yun Liu ◽

Shee-Uan Chen ◽

Kun-Teng Wang ◽

L. Jeffrey Medeiros ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Killer Cell ◽

Cell Lineage ◽

Lymphoid Cells ◽

Terminal Deoxynucleotidyl Transferase ◽

Gene Rearrangements

AbstractMost lymphoblastic lymphomas (LBLs) are regarded as neoplasms of immature T cells because they express cytoplasmic CD3 and frequently carry T-cell receptor (TCR) gene rearrangements. Immature natural killer (NK) and T cells, however, have a common bipotent T/NK-cell precursor in the thymus, and NK cells also express cytoplasmic CD3. Thus, some LBLs could arise from immature NK cells. Mature NK cells express 2 CD94 transcripts: 1A, induced by interleukin 15 (IL-15), and 1B constitutively. Because immature NK cells require IL-15 for development, CD94 1A transcripts could be a marker of NK-LBL. To test this hypothesis, we used laser capture microdissection to isolate IL-15 receptor α+ lymphoid cells from the thymus and showed that these cells contained CD94 1A transcripts. We then assessed for CD94 transcripts in 21 cases of LBL that were cytoplasmic CD3+, nuclear terminal deoxynucleotidyl transferase positive (TdT+), and CD56-, consistent with either the T-cell or NK-cell lineage. We found that 7 LBLs expressed CD94 1A transcripts without TCR gene rearrangements, suggesting NK-cell lineage. Patients with NK-LBL were younger than patients with T-LBL (15 years versus 33 years; P = .11) and had a better 2-year survival (100% versus 27%; P < .01). These results improve the current classification of LBL and contribute to our understanding of NK-cell differentiation.

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

Immunity ◽

10.1016/j.immuni.2014.10.021 ◽

2014 ◽

Vol 41 (6) ◽

pp. 934-946 ◽

Cited By ~ 18

Author(s):

Sang-Yun Lee ◽

Francis Coffey ◽

Shawn P. Fahl ◽

Suraj Peri ◽

Michele Rhodes ◽

...

Keyword(s):

T Cell ◽

Cell Lineage ◽

Γδ T Cell

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The sialyltransferase ST3Gal-IV guides murine T-cell progenitors to the thymus

Blood Advances ◽

10.1182/bloodadvances.2019001046 ◽

2020 ◽

Vol 4 (9) ◽

pp. 1930-1941

Author(s):

Selina Sitte ◽

Daniela Doehler ◽

Markus Sperandio ◽

Jamey D. Marth ◽

David Voehringer

Keyword(s):

Bone Marrow ◽

T Cell ◽

Critical Role ◽

Cell Lineage ◽

Cell Compartment ◽

Hematopoietic Stem ◽

T Cell Progenitors ◽

Further Development ◽

Lymphocyte Populations

Abstract T lymphocytes are important players in beneficial and detrimental immune responses. In contrast to other lymphocyte populations that develop in the bone marrow, T-cell precursors need to migrate to the thymus for further development. The interaction of P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) is crucial for thymic entry of T-cell precursors during settings of T-cell lineage reconstitution. PSGL-1 has to be sialylated to function as a ligand for P-selectin, and the sialyltransferase ST3Gal-IV might play a critical role in this process. We therefore investigated the role of ST3Gal-IV for T-cell development using competitive mixed bone marrow chimeric mice. We found that ST3Gal-IV is dispensable for homing and engraftment of hematopoietic precursors in the bone marrow. However, ST3Gal-IV deficiency affects seeding of the thymus by early T-cell progenitors, leading to impaired restoration of the peripheral T-cell compartment. This defect could be restored by ectopic retroviral expression of ST3Gal-IV in hematopoietic stem cells derived from ST3Gal-IV–deficient donor mice. Our findings show that ST3Gal-IV plays a critical and nonredundant role for efficient T-cell lineage reconstitution after bone marrow transplantation.

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