A cd3− subset of cd4−8+ thymocytes: a rapidly cycling intermediate in the generation of cd4+8+ cells

MacDonald, H. Robson; Budd, Ralph C.; Howe, Rawleigh

doi:10.1002/eji.1830180405

Cited by 140 publications

(81 citation statements)

References 27 publications

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“…During the DN-to-DP transition, DN4 cells in wild-type mice first differentiate into a proliferative TCRβ lo CD8 ISP stage prior to becoming DP cells (MacDonald et al 1988). Similar to observations in other mutant strains (Harker et al 2002;Naito et al 2007), this TCRβ lo CD8 ISP population was difficult to detect in Ikzf1 ΔF4/ΔF4 mice (Fig.…”

Section: Reduced Double-negative (Dn) Thymocytes In Ikzf1 δF4/δf4 Micesupporting

confidence: 74%

Regulation of gene expression dynamics during developmental transitions by the Ikaros transcription factor

2015

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The DNA-binding protein Ikaros is a potent tumor suppressor and hematopoietic regulator. However, the mechanisms by which Ikaros functions remain poorly understood, due in part to its atypical DNA-binding properties and partnership with the poorly understood Mi-2/NuRD complex. In this study, we analyzed five sequential stages of thymocyte development in a mouse strain containing a targeted deletion of Ikaros zinc finger 4, which exhibits a select subset of abnormalities observed in Ikaros-null mice. By examining thymopoiesis in vivo and in vitro, diverse abnormalities were observed at each developmental stage. RNA sequencing revealed that each stage is characterized by the misregulation of a limited number of genes, with a strong preference for stage-specific rather than lineagespecific genes. Strikingly, individual genes rarely exhibited Ikaros dependence at all stages. Instead, a consistent feature of the aberrantly expressed genes was a reduced magnitude of expression level change during developmental transitions. These results, combined with analyses of the interplay between Ikaros loss of function and Notch signaling, suggest that Ikaros may not be a conventional activator or repressor of defined sets of genes. Instead, a primary function may be to sharpen the dynamic range of gene expression changes during developmental transitions via atypical molecular mechanisms that remain undefined.

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Section: Reduced Double-negative (Dn) Thymocytes In Ikzf1 δF4/δf4 Micesupporting

confidence: 74%

Regulation of gene expression dynamics during developmental transitions by the Ikaros transcription factor

2015

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“…They emerge after DN cells and before DP cells and are programmed to differentiate into DP cells. These similarities indicate their similar stages of differential pathways from DN to DP cells [14,15,17]. The choice of the "CD8 pathway" or CD4 pathway seems to be genetically destined, with one pathway dominant in one strain of mice [15,16].…”

Section: Discussionmentioning

confidence: 96%

“…Immature CD4 and CD8 single positive (ISP) thymocytes have been recognized and studied intensively during the 1980s and 1990s [12][13][14][15][16]. They have been shown to share great similarities, both being blastic, rapidly cycling, cortisone sensitive, localized in the outer thymic cortex and making up very little proportion in adult mice.…”

Section: Discussionmentioning

confidence: 99%

Kinetics of thymocyte developmental process in fetal and neonatal mice

Xiao

Chen

2003

Cell Res

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Kinetics of thymocyte development in vivo during embryogenesis was pursued. The early development of thymocytes in the fetal and neonatal BALB/c mice was discontinuous, with four waves of cell proliferation occurring at fetal day (Fd) 14 to 17, Fd 18 to day (D) 1 after birth, D 2 to D 5 and D6 thereafter. The first three proliferation waves coincided with the generation of CD4 hi CD8 hi (DP), TCR + CD4 hi CD8 -/lo (CD4 SP), and TCR + CD4 -/lo CD8 int/hi (CD8 SP) thymocytes, respectively. The transition from DN to DP cells was further investigated and it was found out that there were two differential pathways via immature single positive (ISP) cells in the BALB/c mice, each functioning at different fetal ages. One is via TCR -CD4 -CD8 + cells, occurring between Fd 15 and Fd 17 and the other is via TCR -CD4 + CD8 -cells, occurring from Fd 17 until birth. In contrast, the TCR -CD4 -CD8 + pathway dominated overwhelmingly in the C57BL/6 mice. These findings shed new light on the hypothesis that the differential pathway preference varies with mouse strains. With respect to the shift in the intensity of CD4 and CD8 expression on thymocytes from fetal to adult mice, the TCR + CD4 hi CD8 -/lo , and TCR + CD4 -/lo CD8 int/hi subsets might be equivalent to the medullary type TCR + CD4/CD8 SP cells.

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“…This kinetic pattern contrasts with the behaviors of other three subsets in which a considerable recovery is attained by Day 14. Recent studies have demonstrated that very transient CD3-CD4-CD8+SP cycling cells in the thymus represent an intermediate between DN and DP cells MacDonald et al 1988). So, we must take a possible reduction of this intermediate subset into consideration.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of a single dose of cyclophosphamide on T cell subsets of the thymus and spleen in mice: flow cytofluorometry analysis.

Miyauchi

Kiramine²,

Tanaka

et al. 1990

Tohoku J. Exp. Med.

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Sequential changes in the distribution of lymphocyte subpopulations of the thymus and spleen in BALB/c mice (male, 8-weeks old) during 2 weeks after a single i.p, injection of cyclophosphamide (CY, 200 mg kg body weight) were studied mainly through the use of CD4, CD8 and CD3-E markers together with single-or two-color flow cytofluorometry. In the thymus on Day 2 after CY treatment, a marked decrease in the number and proportion of PNAh', CD3-and CD4+CD8+ double positive (DP) subpopulation was observed in parallel with a marked reduction in the thymus weight, cortical area and total thymocyte number. This phenomenon might be associated with the decrease in the percentage of thymocytes at the S phase of the cell cycle on Day 1 and 2 after CY treatment, owing to the depletion of the rapidly dividing cells in DP subset. There was a significant reduction in the number and proportion in CD4+ single positive(SP) subset on Day 7. The cell number of CD8+SP subset continued to decrease during Day 7 to Day 14. This contrasted with the behaviors of DP, CD4+SP and CD4-CD8-double negative (DN) subsets in which a considerable recovery was attained by Day 14. The spleen from CY-treated mice showed a marked decrease in the DN subset and surface immunoglobulin-positive cells, perhaps B lymphocytes, in both the percentage and the absolute cell number on Days 2 and 7, which paralleled the marked reduction in its weight and total cell number. The absolute cell numbers of CD4+SP and CD8+SP subsets in the spleen were also reduced on Days 2 and 7. The reduction of the CD4+SP/CD8+SP ratio was found in the thymocytes on Days 2 and 7 but not in spleen cells. Our results suggest that the principal target cell population of CY is the PNAh', CD3-and DP immature cortical thymocytes as well as splenic B cells. The sustained decrease in the number of CD8+SP thymocytes after CY treatment might be in part relevant to the potentiating effect of CY pretreatment on immune responses.

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A cd3⁻ subset of cd4⁻8⁺ thymocytes: a rapidly cycling intermediate in the generation of cd4⁺8⁺ cells

Cited by 140 publications

References 27 publications

Regulation of gene expression dynamics during developmental transitions by the Ikaros transcription factor

Regulation of gene expression dynamics during developmental transitions by the Ikaros transcription factor

Kinetics of thymocyte developmental process in fetal and neonatal mice

Differential effects of a single dose of cyclophosphamide on T cell subsets of the thymus and spleen in mice: flow cytofluorometry analysis.

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