Genetic Dissection of Vα14Jα18 Natural T Cell Number and Function in Autoimmune-Prone Mice

Matsuki, Naoto; Stanic, Aleksandar K.; Embers, Monica E.; Kaer, Luc Van; Morel, Laurence; Joyce, Sebastian

doi:10.4049/jimmunol.170.11.5429

Cited by 41 publications

(66 citation statements)

References 58 publications

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“…25 NOD genes contributing to this immunodeficiency have been reported in the Idd4, Idd5, Idd9.1 and Idd13 regions, regions distinguishing NOR from NOD. 26,27 Certain of the immune anomalies associated with NOD antigen-presenting cells (APC) also are more normal in NOR, including NF-kB regulation that promotes more normal control of IL-12p70, TNFa and IL-1a cytokine secretion. 28 Thus, a combination of NOR genes serve to suppress autoimmune diabetes development at both the T-cell and APC levels.…”

Section: Discussionmentioning

confidence: 99%

Conditioning the genome identifies additional diabetes resistance loci in Type I diabetes resistant NOR/Lt mice

Reifsnyder

Silveira

et al. 2005

Genes Immun

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While sharing the H2 g7 MHC and many other important Type I diabetes susceptibility (Idd) genes with NOD mice, the NOR strain remains disease free due to resistance alleles within the B12% portion of their genome that is of C57BLKS/J origin. Previous F2 segregation analyses indicated multiple genes within the 'Idd13' locus on Chromosome 2 provide the primary component of NOR diabetes resistance. However, it was clear other genes also contribute to NOR diabetes resistance, but were difficult to detect in the original segregation analyses because they were relatively weak compared to the strong Idd13 protection component. To identify these further genetic components of diabetes resistance, we performed a new F2 segregation analyses in which NOD mice were outcrossed to a 'genome-conditioned' NOR stock in which a large component of Idd13-mediated resistance was replaced with NOD alleles. These F2 segregation studies combined with subsequent congenic analyses confirmed the presence of additional NOR resistance genes on Chr. 1 and Chr. 4, and also potentially on Chr. 11. These findings emphasize the value for diabetes gene discovery of stratifying not only MHC loci conferring the highest relative risk but also as many as possible of the non-MHC loci presumed to contribute significantly.

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Section: Discussionmentioning

confidence: 99%

Conditioning the genome identifies additional diabetes resistance loci in Type I diabetes resistant NOR/Lt mice

Reifsnyder

Silveira

et al. 2005

Genes Immun

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“…As no NKT cell defects were reported in B6.Sle2 mice, the NZB region can be further localized to a 12.1-100.5 Mb interval indicating that the B1a phenotype can be genetically dissected from the NKT cell phenotype (15). Interestingly, NOD congenic studies have identified a locus, Idd9.1 (88.0 -135.8 Mb), which controls the number of NKT cells on chromosome 4 (38). Generation of additional subcongenic mice will be required to determine whether the observed NKT cell phenotype arises from the same genetic locus.…”

Section: Discussionmentioning

confidence: 99%

Dissociation of the Genetic Loci Leading to B1a and NKT Cell Expansions from Autoantibody Production and Renal Disease in B6 Mice with an Introgressed New Zealand Black Chromosome 4 Interval

Loh

Cai

Bonventi

et al. 2007

The Journal of Immunology

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Previous mapping studies have linked New Zealand Black (NZB) chromosome 4 to several lupus traits, including autoantibody production, splenomegaly, and glomerulonephritis. To confirm the presence of these traits, our laboratory introgressed homozygous NZB chromosome 4 intervals extending from either 114 to 149 Mb or 32 to 149 Mb onto the lupus-resistant C57BL/6 background (denoted B6.NZBc4S and B6.NZBc4L, respectively). Characterization of aged cohorts revealed that B6.NZBc4L mice exhibited a striking increase in splenic B1a and NKT cells in the absence of high titer autoantibody production and significant renal disease. Tissue-specific expansion of these subsets was also seen in the peritoneum and liver for B1a cells and in the bone marrow for NKT cells. Staining with CD1d tetramers loaded with an α-galactosylceramide analog (PBS57) demonstrated that the expanded NKT cell population was mainly CD1d-dependent NKT cells. The lack of both cellular phenotypes in B6.NZBc4S mice demonstrates that the genetic polymorphism(s) that result in these phenotypes are on the proximal region of NZB chromosome 4. This study confirms the presence of a locus that promotes the expansion of B1a cells and newly identifies a region that promotes CD1d-restricted NKT cell expansion on NZB chromosome 4. Taken together, the data indicate that neither an expansion of B1a cells and/nor NKT cells is sufficient to promote autoantibody production and ultimately, renal disease.

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“…thymocytes and cocultured in triplicate for 18 -20 h at 37°C. IL-2 secreted upon activation of the hybridoma was monitored by ELISA (9).…”

Section: C57bl/6 and B6129-nf-b1mentioning

confidence: 99%

“…with 10 g of ␣GalCer diluted in PBS from a 200 g/ml stock solution in vehicle (0.05% v/v polysorbate-20 and 0.9% w/v NaCl) or vehicle. Four hours later, sera were collected, and IL-2, IL-4, and IFN-␥ were measured by ELISA (9).…”

Section: Measurement Of Cytokine Responsesmentioning

confidence: 99%

Cutting Edge: The Ontogeny and Function of Va14Ja18 Natural T Lymphocytes Require Signal Processing by Protein Kinase Cθ and NF-κB

Stanic

Bezbradica

Park

et al. 2004

The Journal of Immunology

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The rapid and robust immunoregulatory cytokine response of Va14Ja18 natural T (iNKT) cells to glycolipid Ags determines their diverse functions. Unlike conventional T cells, iNKT lymphocyte ontogeny absolutely requires NF-κB signaling. However, the precise role of NF-κB in iNKT cell function and the identity of upstream signals that activate NF-κB in this T cell subset remain unknown. Using mice in which iNKT cell ontogeny has been rescued despite inhibition of NF-κB signaling, we demonstrate that iNKT cell function requires NF-κB in a lymphocyte-intrinsic manner. Furthermore, the ontogeny of functional iNKT cells requires signaling through protein kinase Cθ, which is dispensable for conventional T lymphocyte development. The unique requirement of protein kinase Cθ implies that signals emanating from the TCR activate NF-κB during iNKT cell development and function. Thus, we conclude that NF-κB signaling plays a crucial role at distinct levels of iNKT cell biology.

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Genetic Dissection of Vα14Jα18 Natural T Cell Number and Function in Autoimmune-Prone Mice

Cited by 41 publications

References 58 publications

Conditioning the genome identifies additional diabetes resistance loci in Type I diabetes resistant NOR/Lt mice

Conditioning the genome identifies additional diabetes resistance loci in Type I diabetes resistant NOR/Lt mice

Dissociation of the Genetic Loci Leading to B1a and NKT Cell Expansions from Autoantibody Production and Renal Disease in B6 Mice with an Introgressed New Zealand Black Chromosome 4 Interval

Cutting Edge: The Ontogeny and Function of Va14Ja18 Natural T Lymphocytes Require Signal Processing by Protein Kinase Cθ and NF-κB

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