Variation in the <i>Cd3ζ</i> (<i>Cd247</i>) Gene Correlates with Altered T Cell Activation and Is Associated with Autoimmune Diabetes

Lundholm, Marie; Mayans, Sofia; Motta, Vinı́cius; Löfgren-Burström, Anna; Danska, Jayne S.; Holmberg, Dan

doi:10.4049/jimmunol.0904012

Cited by 35 publications

(34 citation statements)

References 53 publications

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“…2 B and D); this decreased phosphorylation did not result from a difference in total CD3ζ between B6 g7 and NOD T cells (Fig. S1), which is in accordance with the work by Lundholm et al (18). We conducted a control experiment with cells from B6 (CD45.2) and B6.CD45.1 congenic mice to evaluate the contribution of technical variation.…”

Section: Resultssupporting

confidence: 89%

Single-cell mass cytometry of TCR signaling: Amplification of small initial differences results in low ERK activation in NOD mice

Mingueneau

Krishnaswamy

Spitzer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Signaling from the T-cell receptor (TCR) conditions T-cell differentiation and activation, requiring exquisite sensitivity and discrimination. Using mass cytometry, a high-dimensional technique that can probe multiple signaling nodes at the single-cell level, we interrogate TCR signaling dynamics in control C57BL/6 and autoimmunity-prone nonobese diabetic (NOD) mice, which show ineffective ERK activation after TCR triggering. By quantitating signals at multiple steps along the signaling cascade and parsing the phosphorylation level of each node as a function of its predecessors, we show that a small impairment in initial pCD3ζ activation resonates farther down the signaling cascade and results in larger defects in activation of the ERK1/2-S6 and IκBα modules. This nonlinear property of TCR signaling networks, which magnifies small initial differences during signal propagation, also applies in cells from B6 mice activated at different levels of intensity. Impairment in pCD3ζ and pSLP76 is not a feedback consequence of a primary deficiency in ERK activation because no proximal signaling defect was observed in Erk2 KO T cells. These defects, which were manifest at all stages of T-cell differentiation from early thymic pre-T cells to memory T cells, may condition the imbalanced immunoregulation and tolerance in NOD T cells. More generally, this amplification of small initial differences in signal intensity may explain how T cells discriminate between closely related ligands and adopt strongly delineated cell fates.

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Section: Resultssupporting

confidence: 89%

Single-cell mass cytometry of TCR signaling: Amplification of small initial differences results in low ERK activation in NOD mice

Mingueneau

Krishnaswamy

Spitzer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…[37][38][39] Although causal effects of these SNPs on CD247 expression and function have not been completely characterized, variation in this gene correlated with altered T-cell activation and autoimmune diabetes in mice. 40 In our study, the rs2056626 G minor allele in both recipients and donors showed allelic and dominant associations with increased risk of sclerosis in patients with chronic GVHD. These results suggest that variable expression of CD3z might play a pathogenic role in sclerotic GVHD and other autoimmune diseases by altering TCR signaling.…”

Section: Discussionmentioning

confidence: 88%

Genetic risk factors for sclerotic graft-versus-host disease

Inamoto

Martin

Flowers

et al. 2016

Blood

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“…As a member of the "red-complex" bacteria, P. gingivalis primarily inhabits the gingival crevices (27,37). The major component of crevicular fluid is plasma (41). The total sialic acid in the plasma is quite abundant (ϳ2 mM).…”

Section: Discussionmentioning

confidence: 99%

Abrogation of Neuraminidase Reduces Biofilm Formation, Capsule Biosynthesis, and Virulence of Porphyromonas gingivalis

Kurniyati

Hu³

et al. 2012

Infect Immun

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The oral bacterium Porphyromonas gingivalis is a key etiological agent of human periodontitis, a prevalent chronic disease that affects up to 80% of the adult population worldwide. P. gingivalis exhibits neuraminidase activity. However, the enzyme responsible for this activity, its biochemical features, and its role in the physiology and virulence of P. gingivalis remain elusive. In this report, we found that P. gingivalis encodes a neuraminidase, PG0352 (Sia Pg ). Transcriptional analysis showed that PG0352 is monocistronic and is regulated by a sigma 70 -like promoter. Biochemical analyses demonstrated that Sia Pg is an exo-␣-neuraminidase that cleaves glycosidic-linked sialic acids. Cryoelectron microscopy and tomography analyses revealed that the PG0352 deletion mutant (⌬PG352) failed to produce an intact capsule layer. Compared to the wild type, in vitro studies showed that ⌬PG352 formed less biofilm and was less resistant to killing by the host complement. In vivo studies showed that while the wild type caused a spreading type of infection that affected multiple organs and all infected mice were killed, ⌬PG352 only caused localized infection and all animals survived. Taken together, these results demonstrate that Sia Pg is an important virulence factor that contributes to the biofilm formation, capsule biosynthesis, and pathogenicity of P. gingivalis, and it can potentially serve as a new target for developing therapeutic agents against P. gingivalis infection.

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Variation in the Cd3ζ (Cd247) Gene Correlates with Altered T Cell Activation and Is Associated with Autoimmune Diabetes

Abstract: Material Supplementary 2.DC1http://www.jimmunol.org/content/suppl/2010/04/16/jimmunol.090401

Cited by 35 publications

References 53 publications

Single-cell mass cytometry of TCR signaling: Amplification of small initial differences results in low ERK activation in NOD mice

Single-cell mass cytometry of TCR signaling: Amplification of small initial differences results in low ERK activation in NOD mice

Genetic risk factors for sclerotic graft-versus-host disease

Abrogation of Neuraminidase Reduces Biofilm Formation, Capsule Biosynthesis, and Virulence of Porphyromonas gingivalis

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