Ikaros Null Mice Display Defects in T Cell Selection and CD4 versus CD8 Lineage Decisions

Urban, Julie; Winandy, Susan

doi:10.4049/jimmunol.173.7.4470

Cited by 39 publications

(55 citation statements)

References 34 publications

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“…We also observed inappropriate production of CD4SP cells in Rag1 Ϫ/Ϫ HYTCRtgGli3 ϩ/Ϫ thymus. Similar observation has been reported previously for Rag Ϫ/Ϫ HYTCRtg Ikaros null thymus (51). In the case of the Ikaros null thymus, the existence of CD4SP cells expressing a TCR interacting with MHC class I-presented ligand was attributed to reduced signal strength, whereas no reduction in apoptosis was observed.…”

Section: Discussionsupporting

confidence: 74%

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The Gli3 Transcription Factor Expressed in the Thymus Stroma Controls Thymocyte Negative Selection Via Hedgehog-Dependent and -Independent Mechanisms

Hager-Theodorides

Furmanski²,

Ross³

et al. 2009

The Journal of Immunology

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The Hedgehog (Hh) responsive transcription factor Gli3 is required for efficient thymocyte development in the fetus. In this study we show that Gli3, not detected in adult thymocytes, is expressed in the murine fetal and adult thymus stroma. PCR array analysis revealed Cxcl9, Rbp1, and Nos2 as novel target genes of Gli3. We show that Gli3 positively regulates the expression of these genes, most likely by suppressing an intermediate repressor. Deletion of autoreactive thymocytes depends on their interactions with the thymus stroma. Repression of the proapoptotic gene Nos2 in Gli3 mutants coincides with reduced apoptosis of double positive thymocytes undergoing negative selection in vitro and in vivo, and the production of autoreactive thymocytes. Taken together these data indicate that Gli3 controls thymocyte apoptosis and negative selection possibly via the regulation of Nos2. Defective Gli3 expression in the thymus stroma also resulted in decreased CD5 expression on mature thymocytes and inappropriate production of MHC class I-selected CD4+ cells, both consistent with reduced TCR signal strength. Overall our data indicate that Gli3 expressed in the thymus stroma regulates negative selection and TCR signal strength via Hh-dependent and -independent mechanisms, with implications for autoimmunity.

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Section: Discussionsupporting

confidence: 74%

“…The presence of CD4SP cells both in the thymus and the lymph nodes of Rag1 Ϫ/Ϫ HYTCRtgGli3 ϩ/Ϫ animals seemed surprising. Nevertheless, it has been previously shown that autoreactive CD4SP cells can be positively selected via MHC class I-restricted ␣␤TCR (51,52). This lineage diversion is attributed to decreased TCR signal strength.…”

Section: Hytcrtggli3mentioning

confidence: 99%

The Gli3 Transcription Factor Expressed in the Thymus Stroma Controls Thymocyte Negative Selection Via Hedgehog-Dependent and -Independent Mechanisms

Hager-Theodorides

Furmanski²,

Ross³

et al. 2009

The Journal of Immunology

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“…Autoreactive antibodies could be the result of defective negative selection (breakdown of central tolerance) or breakdown of peripheral B cell tolerance. In support of the former hypothesis, T cells in Ikaros-null mice do not undergo negative selection [27].…”

Section: Altered Lymphocyte Populations But No Leukemogenesis In Old mentioning

confidence: 71%

“…It has been hypothesized that Ikaros levels set signaling thresholds for activation in T cells [13,27,28]. It may play a similar role in B cells, since there are common pathways put into motion in B and T cells for regulation of proliferation in response to activation signals; these include the MAP kinase, PI-3 kinase and PLC-c pathways [29].…”

Section: Altered Lymphocyte Populations But No Leukemogenesis In Old mentioning

confidence: 99%

Expression of a non‐DNA‐binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis

et al. 2007

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Ikaros is a transcriptional regulator whose function is essential for B cell development. It is expressed in the hematopoietic stem cell (HSC) through the mature B cell stage. Using genetically engineered mice in which the endogenous Ikaros gene is disrupted, it has been shown that a lack of Ikaros leads to a block in B cell development and that its severe diminution results in a hyperresponsive B cell compartment. Ikaros expression within the HSC has led to speculation as to whether the role of Ikaros in B cell biology is largely accomplished prior to B cell specification. In addition, widespread expression of Ikaros in hematopoietic cells leads to the possibility that some or all of the observed defects are not B cell autonomous. In this report, we demonstrate that over-expression of a dominant interfering Ikaros isoform exclusively in B cells has profound effects on mature B cell function. We provide evidence that continued high-level expression of Ikaros is essential for homeostasis of peripheral lymphocytes and maintenance of B cell tolerance. We also show that deregulation of Ikaros activity does not rapidly result in B cell leukemogenesis as it does with 100% penetrance within the T cell lineage.

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“…For B, E, and G, ( * ) P < 0.05; ( * * ) P < 0.01; ( * * * ) P < 0.001. Winandy 2004). In addition, Ikaros mutant strains contain a thymic CD4 SP population that exhibits immature characteristics, including low levels of TCR expression and the absence of maturation markers (Harker et al 2002;Naito et al 2007).…”

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

confidence: 99%

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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Ikaros Null Mice Display Defects in T Cell Selection and CD4 versus CD8 Lineage Decisions

Cited by 39 publications

References 34 publications

The Gli3 Transcription Factor Expressed in the Thymus Stroma Controls Thymocyte Negative Selection Via Hedgehog-Dependent and -Independent Mechanisms

The Gli3 Transcription Factor Expressed in the Thymus Stroma Controls Thymocyte Negative Selection Via Hedgehog-Dependent and -Independent Mechanisms

Expression of a non‐DNA‐binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis

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

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