Impairment of organ-specific T cell negative selection by diabetes susceptibility genes: genomic analysis by mRNA profiling

Liston, Adrian; Hardy, Kristine; Pittelkow, Yvonne; Wilson, Susan R.; Makaroff, Lydia; Fahrer, Aude M.; Goodnow, Christopher C.

doi:10.1186/gb-2007-8-1-r12

Cited by 39 publications

(28 citation statements)

References 107 publications

(102 reference statements)

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“…Although it is generally accepted that expression of CD69 identifies DP thymocytes recently engaged in positively-selecting TCR-pMHC interactions 3, 65 , it is not clear which (if any) fraction of TCR-triggered CD69 + DP thymocytes is doomed to die following TCR engagement with negatively-selecting pMHC ligands 72-77 . To address this question, we highlighted those genes that have been reproducibly associated with negative selection in TCR transgenic models ( Nr4a1 (NUR77), Bcl2l11 (BIM), Pdcd1 (PD1), and Gadd45b 29, 30, 78 ) on a volcano plot comparing the CD69 + DP and small DP stages (Fig. 6a).…”

Section: Resultsmentioning

confidence: 99%

The transcriptional landscape of αβ T cell differentiation

Mingueneau¹,

Kreslavsky²,

Gray³

et al. 2013

Nat Immunol

267

295

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αβT cell differentiation from thymic precursors is a complex process, explored here with the breadth of ImmGen expression datasets, analyzing how differentiation of thymic precursors gives rise to transcriptomes. After surprisingly gradual changes though early T commitment, transit through the CD4+CD8+ stage involves a shutdown or rare breadth, and correlating tightly with MYC. MHC-driven selection promotes a large-scale transcriptional reactivation. We identify distinct signatures that mark cells destined for positive selection versus apoptotic deletion. Differential expression of surprisingly few genes accompany CD4 or CD8 commitment, a similarity that carries through to peripheral T cells and their activation, revealed by mass cytometry phosphoproteomics. The novel transcripts identified as candidate mediators of key transitions help define the “known unknown” of thymocyte differentiation.

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Section: Resultsmentioning

confidence: 99%

The transcriptional landscape of αβ T cell differentiation

Mingueneau¹,

Kreslavsky²,

Gray³

et al. 2013

Nat Immunol

267

295

View full text Add to dashboard Cite

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“…Variations of another 3 genes could be connected with B cell activation: CD69 was overexpressed 4 fold in IgA tumors (similar to its overexpression polyclonal α1KI B cells) [ 6 , 38 ]); Trim12 (a repressor of lymphocyte activation) [ 39 ] was down-regulated 27 fold in IgA+ tumors, so as the gene for MARCH1, an E3 ubiquitin protein ligase targeting some membrane receptors for degradation and down-regulated by B cell activation [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

The class-specific BCR tonic signal modulates lymphomagenesis in ac-mycderegulation transgenic model

et al. 2014

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Deregulation of c-myc by translocation onto immunoglobulin (Ig) loci can promote B cell malignant proliferations with phenotypes as diverse as acute lymphoid leukemia, Burkitt lymphoma, diffuse large B cell lymphoma, myeloma… The B cell receptor (BCR) normally providing tonic signals for cell survival and mitogenic responses to antigens, can also contribute to lymphomagenesis upon sustained ligand binding or activating mutations. BCR signaling varies among cell compartments and BCR classes. For unknown reasons, some malignancies associate with expression of either IgM or class-switched Ig. We explored whether an IgA BCR, with strong tonic signaling, would affect lymphomagenesis in c-myc IgH 3′RR transgenic mice prone to lymphoproliferations. Breeding c-myc transgenics in a background where IgM expression was replaced with IgA delayed lymphomagenesis. By comparison to single c-myc transgenics, lymphomas from double mutant animals were more differentiated and less aggressive, with an altered transcriptional program. Larger tumor cells more often expressed CD43 and CD138, which culminated in a plasma cell phenotype in 10% of cases. BCR class-specific signals thus appear to modulate lymphomagenesis and may partly explain the observed association of specific Ig classes with human B cell malignancies of differential phenotype, progression and prognosis.

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“…Zfp467 has been identified as an enriched nuclear protein in quiescent leukemic hematopoietic stem cells, implicating Zfp467 as a regulator of hematopoietic stem cell function (71) in addition to the role we have identified in MSC differentiation. In support of Zfp467 playing a role in hematopoiesis, a search for diabetes susceptibility genes found the protein to be a positive regulator of T cell selection in the thymus (71) and thereby associating Zfp467 in T-cell survival and maturation, because defective negative selection for T cell receptor with low self affinity can result in autoimmune diabetes (72)(73)(74).…”

Section: Discussionmentioning

confidence: 99%

Zinc Finger Protein 467 Is a Novel Regulator of Osteoblast and Adipocyte Commitment

Quach

Walker

Allan

et al. 2011

Journal of Biological Chemistry

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Osteoblasts and adipocytes are derived from common mesenchymal progenitor cells. The bone loss of osteoporosis is associated with altered progenitor differentiation from an osteoblastic to an adipocytic lineage. cDNA microarrays and quantitative real-time PCR (Q-PCR) were carried out in a differentiating mouse stromal osteoblastic cell line, Kusa 4b10, to identify gene targets of factors that stimulate osteoblast differentiation including parathyroid hormone (PTH) and gp130-binding cytokines, oncostatin M (OSM) and cardiotrophin-1 (CT-1). Zinc finger protein 467 (Zfp467) was rapidly downregulated by PTH, OSM, and CT-1. Retroviral overexpression and RNA interference for Zfp467 in mouse stromal cells showed that this factor stimulated adipocyte formation and inhibited osteoblast commitment compared with controls. Regulation of adipocyte markers, including peroxisome proliferator-activated receptor (PPAR) ␥, C/EBP␣, adiponectin, and resistin, and late osteoblast/osteocyte markers (osteocalcin and sclerostin) by Zfp467 was confirmed by Q-PCR. Intra-tibial injection of calvarial cells transduced with retroviral Zfp467 doubled the number of marrow adipocytes in C57Bl/6 mice compared with vector control-transduced cells, providing in vivo confirmation of a pro-adipogenic role of Zfp467. Furthermore, Zfp467 transactivated a PPAR-response element reporter construct and recruited a histone deacetylase complex. Thus Zfp467 is a novel co-factor that promotes adipocyte differentiation and suppresses osteoblast differentiation. This has relevance to therapeutic interventions in osteoporosis, including PTH-based therapies currently available, and may be of relevance for the use of adipose-derived stem cells for tissue engineering.Osteoblasts and adipocytes are derived from a common subpopulation of mesenchymal stem cell (MSC) 4 progenitors.MSC lineage commitment is dependent on the expression of key transcription factors that, on induction, initiate a cascade of events culminating in cellular differentiation and development. Among the transcription factors regulated, osteoblast differentiation requires expression of Runx2 (1, 2) to commit progenitors to preosteoblasts, with Osterix (3), ATF4 (4), and AP-1 (5) promoting their transition to functional osteoblasts. Alternately, adipocytic differentiation requires expression of different key regulators, peroxisome proliferator-activated receptor ␥ (PPAR␥) (6) and members of the CCAAT/enhancer-binding protein family (C/EBPs) (7). Because osteoblasts and adipocytes are derived from common progenitors, lineage determination of precursor cells to osteoblasts results in a proportional decrease in adipogenesis. This inverse relationship is observed clinically; an increase in marrow adiposity is associated with age-related osteoporosis (8) and conditions that induce bone loss, such as ovariectomy (9) and immobilization (10). Conversely, high bone mass due to increased osteoblast commitment is associated with reduced adipocyte differentiation (5). The molecular mechanisms by which lineage...

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Impairment of organ-specific T cell negative selection by diabetes susceptibility genes: genomic analysis by mRNA profiling

Cited by 39 publications

References 107 publications

The transcriptional landscape of αβ T cell differentiation

The transcriptional landscape of αβ T cell differentiation

The class-specific BCR tonic signal modulates lymphomagenesis in ac-mycderegulation transgenic model

Zinc Finger Protein 467 Is a Novel Regulator of Osteoblast and Adipocyte Commitment

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