Common Heritable Immunological Variations Revealed in Genetically Diverse Inbred Mouse Strains of the Collaborative Cross

Collin, Roxanne; Balmer, Lois; Morahan, Grant; Lesage, Sylvie

doi:10.4049/jimmunol.1801247

Cited by 33 publications

(35 citation statements)

References 63 publications

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“…Furthermore, previous studies used a wide variety of different mouse strains, with different genetic backgrounds, for the mouse cancer models. Thus, the genetic variation among mouse strains could also contribute to the contradictory conclusions drawn for neutrophil interactions with tumor cells because immune phenotypes vary greatly among mice with different inbred genetic backgrounds 33 , 34 . In particular, mice with different levels of immune system integrity, such as immunocompetent versus immunodeficient mice, were variously utilized in cancer studies focusing on neutrophils 3 , 4 , 13 , 24 .…”

Section: Introductionmentioning

confidence: 99%

Dual roles of neutrophils in metastatic colonization are governed by the host NK cell status

Shi

et al. 2020

Nat Commun

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The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have been reported. In this study, using mouse models of breast cancer, we demonstrate that the metastasis-modulating effects of neutrophils are dictated by the status of host natural killer (NK) cells. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. In contrast, in NK cell-competent mice, neutrophils facilitate metastatic colonization in the same tumor models. In an ex vivo neutrophil-NK cell-tumor cell tri-cell co-culture system, neutrophils are shown to potentially suppress the tumoricidal activity of NK cells, while neutrophils themselves are tumoricidal. Intriguingly, these two modulatory effects by neutrophils are both mediated by reactive oxygen species. Collectively, the absence or presence of NK cells, governs the net tumor-modulatory effects of neutrophils.

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Section: Introductionmentioning

confidence: 99%

Dual roles of neutrophils in metastatic colonization are governed by the host NK cell status

Shi

et al. 2020

Nat Commun

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“…Over the past several years, the CC has been used to model a wide range of biomedically relevant traits including: allergy (Orgel et al 2018), asthma (Donoghue et al 2017), behavior (Chesler 2014; Schoenrock et al 2018; Molenhuis et al 2018), bone development (Levy et al 2015), cancer (Dorman et al 2016; Reilly 2016), cellular immune phenotypes (Graham et al 2017), drug disposition (Nachshon et al 2016), exercise (McMullan et al 2018), fertility (Shorter et al 2017), glucose tolerance (Abu-Toamih Atamni et al 2017; Nashef et al 2017), infectious disease susceptibility (Durrant et al 2011; Ferris et al 2013; Rasmussen et al 2014; Gralinski et al 2015; Graham et al 2015; Graham et al 2016; Gralinski et al 2017; Green et al 2017; Abu Toamih Atamni et al . 2018; Zhang et al 2018; Collin et al 2019), motor performance and body weight (Mao et al 2015), spontaneous colitis (Rogala et al 2014), and toxicology (Cichocki et al 2017; Hartman et al 2017; Mosedale et al 2017; Venkatratnam et al 2017).…”

mentioning

confidence: 99%

Whole Genome Sequencing and Progress Toward Full Inbreeding of the Mouse Collaborative Cross Population

Shorter¹,

Najarian²,

Bell

et al. 2019

G3 Genes|Genomes|Genetics

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Two key features of recombinant inbred panels are well-characterized genomes and reproducibility. Here we report on the sequenced genomes of six additional Collaborative Cross (CC) strains and on inbreeding progress of 72 CC strains. We have previously reported on the sequences of 69 CC strains that were publicly available, bringing the total of CC strains with whole genome sequence up to 75. The sequencing of these six CC strains updates the efforts toward inbreeding undertaken by the UNC Systems Genetics Core. The timing reflects our competing mandates to release to the public as many CC strains as possible while achieving an acceptable level of inbreeding. The new six strains have a higher than average founder contribution from non- domesticus strains than the previously released CC strains. Five of the six strains also have high residual heterozygosity (>14%), which may be related to non- domesticus founder contributions. Finally, we report on updated estimates on residual heterozygosity across the entire CC population using a novel, simple and cost effective genotyping platform on three mice from each strain. We observe a reduction in residual heterozygosity across all previously released CC strains. We discuss the optimal use of different genetic resources available for the CC population.

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“…Quantitation of total NK cells on days 1, 3 and 5 following IP inoculation of PBS or IL-15 are shown in Fig 1B. Following IL-15 treatment, NK cell numbers were dramatically higher on day 1 but progressively decreased over the next 4 days, although remaining significant (p = 0.057) relative to the PBS control throughout ( Fig 1B). Previous studies had shown extremely low numbers of NKT cells in CAST mice compared to classical inbred strains [42]. Indeed, of the eight Collaborative Cross strains, CAST mice had the lowest number of NKT cells (0.060% and 0.067% of total spleen lymphocytes for males and females, respectively).…”

Section: Il-15 Increases Nk and Cd8 + T Cell Numbers In Cast Micementioning

confidence: 88%

Natural killer cells expanded in vivo or ex vivo with IL-15 overcomes the inherent susceptibility of CAST mice to lethal infection with orthopoxviruses

2020

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The wild-derived inbred CAST/EiJ mouse, one of eight founder strains in the Collaborative Cross panel, is an exceptional model for studying monkeypox virus (MPXV), an emerging human pathogen, and other orthopoxviruses including vaccinia virus (VACV). Previous studies suggested that the extreme susceptibility of the CAST mouse to orthopoxviruses is due to an insufficient innate immune response. Here, we focused on the low number of natural killer (NK) cells in the naïve CAST mouse as a contributing factor to this condition. Administration of IL-15 to CAST mice transiently increased NK and CD8 + T cells that could express IFN-γ, indicating that the progenitor cells were capable of responding to cytokines. However, the number of NK cells rapidly declined indicating a defect in their homeostasis. Furthermore, IL-15-treated mice were protected from an otherwise lethal challenge with VACV or MPXV. IL-15 decreased virus spread and delayed death even when CD4 + /CD8 + T cells were depleted with antibody, supporting an early protective role of the expanded NK cells. Purified splenic NK cells from CAST mice proliferated in vitro in response to IL-15 and could be activated with IL-12/IL-18 to secrete interferon-γ. Passive transfer of non-activated or activated CAST NK cells reduced VACV spread but only the latter completely prevented death at the virus dose used. Moreover, antibodies to interferon-γ abrogated the protection by activated NK cells. Thus, the inherent susceptibility of CAST mice to orthopoxviruses can be explained by a low level of NK cells and this vulnerability can be overcome either by expanding their NK cells in vivo with IL-15 or by passive transfer of purified NK cells that were expanded and activated in vitro.

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Common Heritable Immunological Variations Revealed in Genetically Diverse Inbred Mouse Strains of the Collaborative Cross

Cited by 33 publications

References 63 publications

Dual roles of neutrophils in metastatic colonization are governed by the host NK cell status

Dual roles of neutrophils in metastatic colonization are governed by the host NK cell status

Whole Genome Sequencing and Progress Toward Full Inbreeding of the Mouse Collaborative Cross Population

Natural killer cells expanded in vivo or ex vivo with IL-15 overcomes the inherent susceptibility of CAST mice to lethal infection with orthopoxviruses

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