Gimap4 accelerates T-cell death

Schnell, Silke; Démollière, Corinne; Berk, Paul van den; Jacobs, Heinz

doi:10.1182/blood-2005-11-4616

Cited by 70 publications

(130 citation statements)

References 44 publications

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“…Hence, we verify that the rat Gimap4 sequence has undergone a ϳ1800-bp deletion relative to other mammals immediately downstream of the termination codon, with the consequence that a DNA repeat region containing an MTC (mammalian apparent long-terminal repeat retrotransposon (MaLR)) repeat and a rat MER1B repeat is brought in juxtaposition to the end of exon 3 of rat Gimap4. The distinct locations of the poly(A) addition sites in rat and mouse were as predicted by bioinformatics (Table I) and indicate different message sizes for the two species, these being 1.4 kb in rat and 1.7 kb in mouse, the latter agreeing with previous Northern blot data (14,16 with each other, we found just three polymorphisms in addition to the AT insertion within the ORF. The three SNPs are located at positions 1052, 1134, and 1219 in the 3Ј-UTR of the PVG rat (GenBank accession no.…”

Section: A Deletion In the 3ј-untranslated Region (Utr) Of Rat Gimap4supporting

confidence: 81%

“…u ,RT7 b cells showed the profile predicted from earlier studies in mice and rats (14,16,13), namely the absence of Gimap4 expression in CD4 ϩ CD8 ϩ double-positive thymocytes, strong expression in single-positive thymocytes and peripheral T cells, and weaker but significant expression in the double-negative (DN) subset (Fig. 2).…”

Section: Expression Of Gimap4 In Lymphocyte Subsetsmentioning

confidence: 56%

“…Roles in the regulation of cell death have been proposed or demonstrated for members of the Gimap family, most notably in the prosurvival properties of rat Gimap5 (see Introduction); by contrast, recent studies have suggested a prodeath role for Gimap4 in the mouse (11,16). Initial analysis showed no obvious abnormality in the rate of cell death when FACS-purified BN T cells were …”

Section: T Lineage Cells From Bn Rats Display An Unusual Apoptotic Phmentioning

confidence: 99%

“…A more detailed analysis of in vitro apoptotic responses of BN T cells was then performed. This was guided by the recently published analysis of a mouse strain with a targeted deletion in Gimap4 (16). In this study, one of our groups had noticed that T cells from the knockout mice exhibited slower kinetics in the induced "death program" as defined by flow cytometry.…”

Section: Figurementioning

confidence: 99%

“…Using these reagents, we have encountered an unexpected deficiency in Gimap4 protein expression in the inbred Brown Norway (BN) rat, a strain used widely in immunological research as well as in other biomedical disciplines. We also report here functional comparisons of BN rat T lymphocytes with those from mice carrying a targeted deletion in Gimap4, recently described by one of our laboratories (16).…”

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confidence: 99%

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A Natural Hypomorphic Variant of the Apoptosis Regulator Gimap4/IAN1

Carter

Dion

Schnell

et al. 2007

The Journal of Immunology

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The Gimap/IAN family of GTPases has been implicated in the regulation of cell survival, particularly in lymphomyeloid cells. Prosurvival and prodeath properties have been described for different family members. We generated novel serological reagents to study the expression in rats of the prodeath family member Gimap4 (IAN1), which is sharply up-regulated at or soon after the stage of T cell-positive selection in the thymus. During these investigations we were surprised to discover a severe deficiency of Gimap4 expression in the inbred Brown Norway (BN) rat. Genetic analysis linked this trait to the Gimap gene cluster on rat chromosome 4, the probable cause being an AT dinucleotide insertion in the BN Gimap4 allele (AT(+)). This allele encodes a truncated form of Gimap4 that is missing 21 carboxyl-terminal residues relative to wild type. The low protein expression associated with this allele appears to have a posttranscriptional cause, because mRNA expression was apparently normal. Spontaneous and induced apoptosis of BN and wild-type T cells was analyzed in vitro and compared with the recently described mouse Gimap4 knockout. This revealed a “delayed” apoptosis phenotype similar to but less marked than that of the knockout. The Gimap4 AT(+) allele found in BN was shown to be rare in inbred rat strains. Nevertheless, when wild rat DNA samples were studied the AT(+) allele was found at a high overall frequency (∼30%). This suggests an adaptive significance for this hypomorphic allele.

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Section: A Deletion In the 3ј-untranslated Region (Utr) Of Rat Gimap4supporting

confidence: 81%

Section: Expression Of Gimap4 In Lymphocyte Subsetsmentioning

confidence: 56%

Section: T Lineage Cells From Bn Rats Display An Unusual Apoptotic Phmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

mentioning

confidence: 99%

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A Natural Hypomorphic Variant of the Apoptosis Regulator Gimap4/IAN1

Carter

Dion

Schnell

et al. 2007

The Journal of Immunology

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Gimap3 and Gimap5 cooperate to maintain T‐cell numbers in the mouse

et al. 2013

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Gimap3 (IAN4) and Gimap5 (IAN5) are highly homologous GTP-binding proteins of the Gimap family. Gimap3 and Gimap5, whose transcripts are abundant in mature lymphocytes, can associate with antiapoptotic Bcl-2 family proteins. While it is established that Gimap5 regulates T-cell survival, the in vivo role of Gimap3 is unclear. Here we report the preparation and characteristics of mouse strains lacking Gimap3 and/or Gimap5. We found that the number of T cells was markedly reduced in mice deficient in both Gimap3 and Gimap5. The defects in T-cell cellularity were more severe in mice lacking both Gimap3 and Gimap5 than in mice lacking only Gimap5. No defects in the cellularity of T cells were detected in mice lacking only Gimap3, whereas bone marrow cells from Gimap3-deficient mice showed reduced T-cell production in a competitive hematopoietic environment. Moreover, retroviral overexpression and short hairpin RNAs-mediated silencing of Gimap3 in bone marrow cells elevated and reduced, respectively, the number of T cells produced in irradiated mice. These results suggest that Gimap3 is a regulator of T-cell numbers in the mouse and that multiple Gimap family proteins cooperate to maintain T-cell survival.

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Survival of mature T cells in the periphery is intrinsically dependent on GIMAP1 in mice

et al. 2016

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An effective immune system depends upon the survival of mature T cells in the periphery. Members of the GIMAP family of GTPases have been proposed to regulate this homeostasis, supported by the paucity of peripheral T cells in rodents deficient for either GIMAP1 or GIMAP5. It is unclear whether this lack of T cells is a consequence of an ontological defect, causing the thymus to generate and export T cells incapable of surviving in the periphery, or whether (alternatively or additionally) mature T cells intrinsically require GIMAP1 for survival. Using the ERT2Cre+ transgene, we conditionally deleted Gimap1 in C57BL/6 mice and demonstrate that GIMAP1 is intrinsically required for the survival of mature T cells in the periphery. We show that, in contrast to GIMAP5, this requirement is independent of the T‐cells' activation status. We investigated the nature of the survival defect in GIMAP1‐deficient CD4+ T cells and show that the death occurring after GIMAP1 ablation is accompanied by mitochondrial depolarization and activation of the extrinsic apoptotic pathway. This study shows that GIMAP1 is critical for maintaining the peripheral T‐cell pool in mice and offers a potent target for the treatment of T‐cell‐mediated diseases.

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Gimap4 accelerates T-cell death

Abstract: Gimap4, a member of the newly identified

Cited by 70 publications

References 44 publications

A Natural Hypomorphic Variant of the Apoptosis Regulator Gimap4/IAN1

A Natural Hypomorphic Variant of the Apoptosis Regulator Gimap4/IAN1

Gimap3 and Gimap5 cooperate to maintain T‐cell numbers in the mouse

Survival of mature T cells in the periphery is intrinsically dependent on GIMAP1 in mice

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