Genetic control of murine invariant natural killer T cells maps to multiple type 1 diabetes regions

Tsaih, Shirng‐Wern; Khaja, Shamim; Ciecko, Ashley E.; Mackinney, Erin; Chen, Yi-Guang

doi:10.1038/gene.2013.32

Cited by 4 publications

(13 citation statements)

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“…NOD and ICR mice have significantly different frequencies and numbers of thymic and splenic iNKT-cells as a result of genetic variations at multiple loci 3 , 23 . We generated bone marrow (BM) chimeras to ask if factors intrinsic to hematopoietic cells respectively suppress and promote iNKT-cell development in NOD and ICR mice.…”

Section: Resultsmentioning

confidence: 99%

“…We previously identified multiple QTL regulating the development of iNKT-cells in a (NOD × ICR)F2 cross 23 . We reasoned that if the expression level of CD1d is a factor that differentially regulates iNKT-cell development in NOD and ICR mice, then a common genetic locus would be identified to control both traits.…”

Section: Resultsmentioning

confidence: 99%

“…Both NOD and ICR/HaJ (hereafter ICR) are related Swiss-derived inbred strains originating from an Ha/ICR outbred stock 22 , but differ significantly in their iNKT-cell frequencies 3 . To further understand the genetic basis of iNKT-cell development, we outcrossed the NOD mouse to the ICR strain and employed an F2 mapping strategy to identify multiple quantitative trait loci (QTL) that regulate the frequencies of thymic and splenic iNKT-cells 23 . We reported that several iNKT-cell QTL co-localized with previously known mouse and human T1D regions.…”

Section: Introductionmentioning

confidence: 99%

“…We reported that several iNKT-cell QTL co-localized with previously known mouse and human T1D regions. These included a Chromosome (Chr) 12 QTL that overlapped with a syntenic human T1D locus on Chr 14 23 . While NOD mice have lower frequencies and numbers of iNKT-cells compared to the ICR strain, our F2 mapping study also identified several loci where NOD alleles promoted rather than suppressed iNKT-cell development 23 .…”

Section: Introductionmentioning

confidence: 99%

“…These included a Chromosome (Chr) 12 QTL that overlapped with a syntenic human T1D locus on Chr 14 23 . While NOD mice have lower frequencies and numbers of iNKT-cells compared to the ICR strain, our F2 mapping study also identified several loci where NOD alleles promoted rather than suppressed iNKT-cell development 23 . These results indicate that in the context of the NOD genome, alleles that normally enhance iNKT-cell development are masked by other defects in this strain.…”

Section: Introductionmentioning

confidence: 99%

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A locus on mouse chromosome 13 inversely regulates CD1d expression and the development of invariant natural killer T-cells

et al. 2015

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Invariant natural killer T (iNKT)-cell development is controlled by many polymorphic genes present in commonly used mouse inbred strains. Development of type 1 diabetes (T1D) in NOD mice partly results from their production of fewer iNKT-cells compared to non-autoimmune prone control strains including ICR. We previously identified several iNKT-cell quantitative trait genetic loci co-localized with known mouse and human T1D regions in a (NOD × ICR)F2 cross. To further dissect the mechanisms underlying the impaired iNKT-cell compartment in NOD mice, we carried out a series of bone marrow transplantation as well as additional genetic mapping studies. We found that impaired iNKT-cell development in NOD mice was mainly due to the inability of their double-positive (DP) thymocytes to efficiently select this T-cell population. Interestingly, we observed higher levels of CD1d expression by NOD than ICR DP thymocytes. The genetic control of the inverse relationship between the CD1d expression level on DP thymocytes and the frequency of thymic iNKT-cells was further mapped to a region on Chromosome 13 between 60.12 Mb and 70.59 Mb. The NOD allele was found to promote CD1d expression and suppress iNKT-cell development. Our results indicate that genetically controlled physiological variation of CD1d expression levels modulates iNKT-cell development.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A locus on mouse chromosome 13 inversely regulates CD1d expression and the development of invariant natural killer T-cells

et al. 2015

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Evidence of genetic epistasis in autoimmune diabetes susceptibility revealed by mouse congenic sublines

Collin

Dugas

Pelletier³

et al. 2021

Immunogenetics

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Susceptibility to autoimmune diabetes is a complex genetic trait. Linkage analyses exploiting the NOD mouse, which spontaneously develops autoimmune diabetes, has proved to be a useful tool for the characterization of some of these traits. In a linkage analysis using 3A9 TCR transgenic mice on both B10.BR and NOD.H2 k backgrounds, we previously determined that both the Idd2 and Idd13 loci were linked to the proportion of immunoregulatory CD4 -CD8double negative (DN) T cells. In addition to Idd2 and Idd13, five other loci showed weak linkage to the proportion of DN T cells. Of interest, in an interim analysis, a locus on chromosome 12 is linked to DN T cell proportion in both the spleen and the lymph nodes. To determine the impact of this locus on DN T cells, we generated two congenic sublines, which we named Chr12P and Chr12D for proximal and distal, respectively. While 3A9 TCR:insHEL NOD.H2 k -Chr12D mice were protected from diabetes, 3A9 TCR:insHEL NOD.H2 k -Chr12P showed an increase in diabetes incidence. Yet, the proportion of DN T cells was similar to the parental 3A9 TCR NOD.H2 k strain for both of these congenic sublines. A genome-wide two dimensional LOD score analysis reveals genetic epistasis between chromosome 12 and the Idd13 locus. Altogether, this study identified further complex genetic interactions in defining the proportion of DN T cells, along with evidence of genetic epistasis within a locus on chromosome 12 influencing autoimmune susceptibility.

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Modulation of TCR signalling components occurs prior to positive selection and lineage commitment in iNKT cells

Dinh

Stanley

Smith

et al. 2021

Sci Rep

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AbstractiNKT cells play a critical role in controlling the strength and character of adaptive and innate immune responses. Their unique functional characteristics are induced by a transcriptional program initiated by positive selection mediated by CD1d expressed by CD4+CD8+ (double positive, DP) thymocytes. Here, using a novel Vα14 TCR transgenic strain bearing greatly expanded numbers of CD24hiCD44loNKT cells, we examined transcriptional events in four immature thymic iNKT cell subsets. A transcriptional regulatory network approach identified transcriptional changes in proximal components of the TCR signalling cascade in DP NKT cells. Subsequently, positive and negative selection, and lineage commitment, occurred at the transition from DP NKT to CD4 NKT. Thus, this study introduces previously unrecognised steps in early NKT cell development, and separates the events associated with modulation of the T cell signalling cascade prior to changes associated with positive selection and lineage commitment.

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Genetic control of murine invariant natural killer T cells maps to multiple type 1 diabetes regions

Cited by 4 publications

References 50 publications

A locus on mouse chromosome 13 inversely regulates CD1d expression and the development of invariant natural killer T-cells

A locus on mouse chromosome 13 inversely regulates CD1d expression and the development of invariant natural killer T-cells

Evidence of genetic epistasis in autoimmune diabetes susceptibility revealed by mouse congenic sublines

Modulation of TCR signalling components occurs prior to positive selection and lineage commitment in iNKT cells

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