Heme Exporter FLVCR Is Required for T Cell Development and Peripheral Survival

Philip, Mary; Funkhouser, Scott A; Chiu, Edison Y.; Phelps, Susan; Delrow, Jeffrey J.; Cox, James E.; Fink, Pamela J.; Abkowitz, Janis L.

doi:10.4049/jimmunol.1402172

Cited by 28 publications

(18 citation statements)

References 46 publications

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“…Because lck-cre + mice differ from WT mice, care should also be taken when interpreting results using only an lck-cre + control. Intriguingly, some investigators reported no differences between lck-cre + or lck-cre 2 mice, whereas others did (17,19,21,(29)(30)(31)(32)(33)(35)(36)(37) (Fig. 6).…”

Section: Discussionmentioning

confidence: 91%

lck-Driven Cre Expression Alters T Cell Development in the Thymus and the Frequencies and Functions of Peripheral T Cell Subsets

Carow

Gao

Coquet

et al. 2016

The Journal of Immunology

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Conditional gene targeting using the bacteriophage-derived Cre recombinase is widely applied for functional gene studies in mice. Mice transgenic for Cre under the control of the lck gene promoter are used to study the role of loxP-targeted genes in T cell development and function. In this article, we show a striking 65% reduction in cellularity, preferential development of γδ versus αβ T cells, and increased expression of IL-7R in the thymus of mice expressing Cre under the proximal lck promoter (lck-cre+ mice). The transition from CD4/CD8 double-negative to double-positive cells was blocked, and lck-cre+ double-positive cells were more prone to apoptosis and showed higher levels of Cre expression. Importantly, numbers of naive T cells were reduced in spleens and lymph nodes of lck-cre+ mice. In contrast, frequencies of γδ T cells, CD44+CD62L− effector T cells, and Foxp3+ regulatory T cells were elevated, as was the frequency of IFN-γ–secreting CD4+ and CD8+ T cells. A literature survey of 332 articles that used lck-cre+ mice for deletion of floxed genes indicated that results are statistically influenced by the control used (lck-cre+ or lck-cre−), more frequently resembling the lck-cre+ phenotype described in this article if lck-cre− controls were used. Altogether, care should be taken when interpreting published results and to properly control targeted gene deletions using the lck-cre+ strain.

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Section: Discussionmentioning

confidence: 91%

lck-Driven Cre Expression Alters T Cell Development in the Thymus and the Frequencies and Functions of Peripheral T Cell Subsets

Carow

Gao

Coquet

et al. 2016

The Journal of Immunology

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“…As a result, heme-containing proteins play crucial roles in all cells (Sawicki et al, 2015); however, heme can also play lineage-specific roles in differentiation (Philip et al, 2015). Proper heme levels are also crucial for normal fetal development, as defects can lead to limb deformities in addition to abnormal erythropoiesis (Keel et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

Planutis

Xue

Trainor³

et al. 2017

Development

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Transcription factor control of cell-specific downstream targets can be significantly altered when the controlling factor is mutated. We show that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/ KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. Even when expressed as a heterozygote, the Nan-EKLF protein accomplishes this by direct binding and aberrant activation of genes encoding secreted factors that exert a negative effect on erythropoiesis and iron use. Our data form the basis for a novel mechanism of physiological deficiency that is relevant to human dyserythropoietic anemia and likely other disease states.

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“…179 Recent reports suggest that FLVCR is also critical in T cell development and survival. 180 While these effects may validate that excess heme is toxic, it may also speak to the necessity of heme secretory pathways in cell and tissue development and ultimately innate immune functionality. Does heme serve a purpose when released from cells, much like HMGB1 and other mediators including cytokines/chemokines or even growth factors?…”

Section: Heme and Ho-1-derived Products: The Balance Between Cell Injmentioning

confidence: 99%

Heme Oxygenase-1 and Carbon Monoxide in the Heart

Otterbein

Foresti

Motterlini

2016

Circulation Research

177

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Understanding the processes governing the ability of the heart to repair and regenerate after injury is crucial for developing translational medical solutions. New avenues of exploration include cardiac cell therapy and cellular reprogramming targeting cell death and regeneration. An attractive possibility is the exploitation of cytoprotective genes that exist solely for self-preservation processes and serve to promote and support cell survival. While the antioxidant and heat shock proteins are included in this category, one enzyme that has received a great deal of attention as a master protective sentinel is heme oxygenase-1 (HO-1), the rate-limiting step in the catabolism of heme into the bioactive signaling molecules carbon monoxide, biliverdin and iron. The remarkable cardioprotective effects ascribed to HO-1 are best evidenced by its ability to regulate inflammatory processes, cellular signaling and mitochondrial function ultimately mitigating myocardial tissue injury and the progression of vascular-proliferative disease. We discuss here new insights into the role of HO-1 and heme on cardiovascular health, and importantly, how they might be leveraged to promote heart repair after injury.

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Heme Exporter FLVCR Is Required for T Cell Development and Peripheral Survival

Cited by 28 publications

References 46 publications

lck-Driven Cre Expression Alters T Cell Development in the Thymus and the Frequencies and Functions of Peripheral T Cell Subsets

lck-Driven Cre Expression Alters T Cell Development in the Thymus and the Frequencies and Functions of Peripheral T Cell Subsets

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

Heme Oxygenase-1 and Carbon Monoxide in the Heart

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