A unique CD8+ T lymphocyte signature in pediatric type 1 diabetes

Hamel, Yamina; Mauvais, François-Xavier; Pham, Hang-Phuong; Marchi, Christophe; Barilleau, Emilie; Waeckel-Énée, Emmanuelle; Arnoux, Jean‐Baptiste; Hartemann, A.; Cordier, Corinne; Mégret, Jérôme; Rocha, Bénédita; Lonlay, Pascale de; Beltrand, Jacques; Six, Adrien; Robert, Jean‐Jacques; Endert, Peter Van

doi:10.1016/j.jaut.2016.06.003

Cited by 9 publications

(8 citation statements)

References 51 publications

(37 reference statements)

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“…Few references can be found in the literature evaluating TGF‐ β production in AD patients; however, the production of this cytokine seems to alleviate AD . TGF‐ β production by TCD8 cells was described as a TCD8 lymphocyte signature in pediatric type 1 diabetes . In this work, the authors revealed that TCD8 cells simultaneously produce TGF‐ β , IL‐10, granzyme B, and perforin, and suggested that this population is an attempt to counteract an especially aggressive inflammatory disease; however, this population was not described in AD patients.…”

Section: Discussionmentioning

confidence: 91%

IgG from atopic dermatitis patients induces IL‐17 and IL‐10 production in infant intrathymic TCD4 and TCD8 cells

et al. 2018

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Section: Discussionmentioning

confidence: 91%

IgG from atopic dermatitis patients induces IL‐17 and IL‐10 production in infant intrathymic TCD4 and TCD8 cells

et al. 2018

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“…Many of these proteins are potential targets of the immune system with implications for the etiology of type 1 diabetes (19 -21), an autoimmune disease characterized by specific T-cell-mediated autoimmune destruction of pancreatic beta cells (22). Both CD4 ϩ and CD8 ϩ T-cell responses against ZnT8 (23)(24)(25)(26)(27) as well as anti-ZnT8 autoantibodies (28) were found in patients or model animals that developed autoimmune diabetes. Cell-or antibody-mediated autoimmune responses may be directly targeted at ZnT8 displayed on the beta cell surface either in a form of processed ZnT8 peptides associated with MHC class I molecules or intact ZnT8 self-antigen.…”

mentioning

confidence: 99%

Coupling of Insulin Secretion and Display of a Granule-resident Zinc Transporter ZnT8 on the Surface of Pancreatic Beta Cells

Huang¹,

Merriman

Zhang

et al. 2017

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinThe islet-specific zinc transporter ZnT8 mediates zinc enrichment in the insulin secretory granules of the pancreatic beta cell. This granular zinc transporter is also a major selfantigen found in type 1 diabetes patients. It is not clear whether ZnT8 can be displayed on the cell surface and how insulin secretion may regulate the level of ZnT8 exposure to extracellular immune surveillance. Here we report specific antibody binding to the extracellular surface of rat insulinoma INS-1E cells that stably expressed a tagged human zinc transporter ZnT8. Flow cytometry analysis after fluorescent antibody labeling revealed strong correlations among the levels of ZnT8 expression, its display on the cell surface, and glucose-stimulated insulin secretion (GSIS). Glucose stimulation increased the surface display of endogenous ZnT8 from a basal level to 32.5% of the housekeeping Na ؉ /K ؉ ATPase on the cell surface, thereby providing direct evidence for a GSIS-dependent surface exposure of the ZnT8 self-antigen. Moreover, the variation in tagged-ZnT8 expression and surface labeling enabled sorting of heterogeneous beta cells to subpopulations that exhibited marked differences in GSIS with parallel changes in endogenous ZnT8 expression. The abundant surface display of endogenous ZnT8 and its coupling to GSIS demonstrated the potential of ZnT8 as a surface biomarker for tracking and isolating functional beta cells in mixed cell populations.

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“…Individuals with type 1 diabetes may have a defect in the removal of aberrant nucleic acids due to reduced granzyme A and/or SET complex expression arising from genetic perturbations in regulatory factors. Indeed reduced granzyme A expression was recently described in children with type 1 diabetes (19).…”

Section: Discussionmentioning

confidence: 91%

“…This finding, together with the recent demonstration that human granzyme A lacks cyotoxic function (15,17), suggests that granzyme A may have further undefined role(s) in vivo (18). It was recently reported that GZMA transcript and protein expression are strongly downregulated in T cells from children with type 1 diabetes compared with control children (19). In vitro, granzyme A activates components of the cytoplasmic SET complex, an endoplasmic reticulum-associated complex linked to DNA degradation and repair (20).…”

mentioning

confidence: 99%

Granzyme A Deficiency Breaks Immune Tolerance and Promotes Autoimmune Diabetes Through a Type I Interferon–Dependent Pathway

et al. 2017

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Granzyme A is a protease implicated in the degradation of intracellular DNA. Nucleotide complexes are known triggers of systemic autoimmunity, but a role in organ-specific autoimmune disease has not been demonstrated. To investigate whether such a mechanism could be an endogenous trigger for autoimmunity, we examined the impact of granzyme A deficiency in the NOD mouse model of autoimmune diabetes. Granzyme A deficiency resulted in an increased incidence in diabetes associated with accumulation of ssDNA in immune cells and induction of an interferon response in pancreatic islets. Central tolerance to proinsulin in transgenic NOD mice was broken on a granzyme A-deficient background. We have identified a novel endogenous trigger for autoimmune diabetes and an in vivo role for granzyme A in maintaining immune tolerance.

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A unique CD8+ T lymphocyte signature in pediatric type 1 diabetes

Cited by 9 publications

References 51 publications

IgG from atopic dermatitis patients induces IL‐17 and IL‐10 production in infant intrathymic TCD4 and TCD8 cells

IgG from atopic dermatitis patients induces IL‐17 and IL‐10 production in infant intrathymic TCD4 and TCD8 cells

Coupling of Insulin Secretion and Display of a Granule-resident Zinc Transporter ZnT8 on the Surface of Pancreatic Beta Cells

Granzyme A Deficiency Breaks Immune Tolerance and Promotes Autoimmune Diabetes Through a Type I Interferon–Dependent Pathway

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