Distinct Phenotype and Function of NK Cells in the Pancreas of Nonobese Diabetic Mice

Brauner, Hanna; Elemans, Marjet; Lemos, Sara; Broberger, Christian; Holmberg, Dan; Flodström‐Tullberg, Malin; Kärre, Klas; Höglund, Petter

doi:10.4049/jimmunol.0804358

Cited by 75 publications

(73 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Activation stimuli normally endow NK cells with cytotoxic function by up-regulating the expression of granzyme B and perforin and the production of effector cytokines such as IFNγ, TNFα, and granulocyte macrophage colony-stimulating factor (GM-CSF) (1,2). However, NK cell hyporesponsiveness has been observed upon prolonged stimulation with strong immune activating signals (5-11) and in various chronic inflammatory and autoimmune diseases including chronic hepatitis (12), tuberculosis (13), AIDS (14), diabetes (15), and systemic onset juvenile rheumatoid arthritis (16). Whether NK cells become dysfunctional through direct or indirect mechanisms is unknown.…”

mentioning

confidence: 99%

Mature natural killer cells with phenotypic and functional alterations accumulate upon sustained stimulation with IL-15/IL-15Rα complexes

Elpek

Rubinstein

Bellemare-Pelletier

et al. 2010

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

109

View full text Add to dashboard Cite

Cytotoxic lymphocytes such as natural killer (NK) and CD8 T cells play important roles in immunosurveillance by killing virally infected or malignant cells. The homeostatic cytokine, IL-15, promotes the development, function, and survival of NK and CD8 T cells. IL-15 is normally presented in trans as a surface complex with IL-15 receptor-alpha-chain (IL-15Rα) by dendritic cells (DCs) and monocytes. Signaling by IL-15 occurs via the IL-2/IL-15 receptor β-chain (CD122) which is expressed primarily by NK1.1 + cells and CD8 T cells. The use of preformed complexes of IL-15 with soluble IL-15Rα complexes to boost the effector function of CD122 + cytolytic lymphocytes such as NK and CD8 T cells has recently gained considerable attention. Here we describe the impact of transient and prolonged in vivo stimulation by IL-15/IL-15Rα complexes on NK and CD8 T cells. Whereas transitory stimulation increased the number of activated NK cells and significantly enhanced their effector function, prolonged stimulation by IL-15/IL-15Rα complexes led to a marked accumulation of mature NK cells with considerably impaired activation, cytotoxicity, and proliferative activity, and an altered balance of activating and inhibitory receptors. In contrast to NK cells, CD8 T cells exhibited an activated phenotype and robust T cell receptor stimulation and effector function upon chronic stimulation with IL-15/IL-15Rα complexes. Thus, prolonged stimulation with the strong activating signal leads to a preferential accrual of mature NK cells with altered activation and diminished functional capacity. These findings point to a negative feedback mechanism to preferentially counterbalance excessive NK cell activity and may have important implications for cytokine immunotherapy.

show abstract

mentioning

confidence: 99%

Mature natural killer cells with phenotypic and functional alterations accumulate upon sustained stimulation with IL-15/IL-15Rα complexes

Elpek

Rubinstein

Bellemare-Pelletier

et al. 2010

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

109

View full text Add to dashboard Cite

show abstract

“…NK cells are lymphocytes that play an important role in the defense against pathogen infections and tumor development, but they have also been shown to participate in autoimmunity [15]. In T1D, NK cells infiltrate the islets at disease onset in both human and murine studies [16,17], but their exact role is still controversial because of conflicting results. It is well known that NK cells from NOD mice have impaired function and defects in activation [18,19].…”

Section: Introductionmentioning

confidence: 99%

“…In T1D, NK cells infiltrate the islets at disease onset in both human and murine studies [16,17], but their exact role is still controversial because of conflicting results. It is well known that NK cells from NOD mice have impaired function and defects in activation [18,19].…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, no effect of depleting NK cells in NOD mice has been reported, and it has even been suggested that the protective effect of complete Freund's adjuvant in NOD mice is mediated by more active NK cells [26,27]. Furthermore, it is known that NK cells infiltrate the prediabetic NOD mouse pancreas before T cells do, and they have a distinct phenotype compared with spleen and pancreatic lymph node (PLN) [17]. However, it is speculated that NK cells function as regulators of autoimmunity [15].…”

mentioning

confidence: 99%

See 1 more Smart Citation

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

et al. 2014

View full text Add to dashboard Cite

Dietary gluten influences the development of type 1 diabetes in nonobese diabetic (NOD) mice and biobreeding rats, and has been shown to influence a wide range of immunological factors in the pancreas and gut. In the present study, the effects of gluten on NK cells were studied in vitro and in vivo. We demonstrated that gliadin increased direct cytotoxicity and IFN-γ secretion from murine splenocytes and NK cells toward the pancreatic beta-cell line MIN6 cells. Additionally, stimulation of MIN6 cells led to a significantly increased proportion of degranulating C57BL/6 CD107a + NK cells. Stimulation of C57BL/6 pancreatic islets with gliadin significantly increased secretion of IL-6 more than ninefold. In vivo, the gluten-containing diet led to a higher expression of NKG2D and CD71 on NKp46 + cells in all lymphoid organs in BALB/c and NOD mice compared with the gluten-free diet. Collectively, our data suggest that dietary gluten increases murine NK-cell activity against pancreatic beta cells. This mechanism may contribute to development of type 1 diabetes and explain the higher disease incidence associated with gluten intake in NOD mice.Keywords: C56BL/6 mice r Gliadin r Gluten r NK cells r NOD mice r Type 1 diabetes Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDietary gluten is the initiating factor in the development of celiac disease (CD), however, an association between CD and type 1 diabetes (T1D) has been established. A gluten-free (GF) diet has been shown to have a protective effect against the development of T1D. It has been demonstrated that a GF diet in nonobese diabetic (NOD) mice reduces diabetes incidence from 64 to 15% [1], and similar results have been obtained with biobreeding rats [2]. Increased intestinal permeability occurs prior to the onset of T1D in both spontaneous animal models and human disease [3,4]. Patients with both CD and T1D diseases carry high-risk HLA alleles [5], and approximately 10% of T1D patients have anCorrespondence: Jesper Larsen e-mail: jelars@gmail.com increased prevalence of CD [6]. Moreover, T1D rarely develops after diagnosed CD, which may be because of the protective effect of a GF diet [7]. A recently published case report describes a boy with T1D who was able to maintain a low fasting blood glucose level without insulin therapy for more than 20 months after the time of diagnosis by adhering to a GF diet [8]. Lately, it has also been suggested that a family of gluten proteins known as gliadins may contribute directly to beta-cell hyperactivity, as enzymatically digested gliadin and a 33-mer gliadin fragment increase insulin secretion from beta cells by affecting the K ATP channel current [9]. This process could induce increased Ag expression of the beta-cell surface and prevent beta-cell rest [10]. Gliadin has been shown to stimulate several components of the adaptive immune system, such as Treg cells, Th17 cells, and DCs [11,12]. Gliadin fragments have also been shown to stimulate TLR4 a...

show abstract

“…Thus, NK cells could contribute directly and indirectly to the destruction of -cells. NK cells have been detected in the pancreas of patients with T1D and in T1D mouse models (Dotta et al, 2007;Alba et al, 2008;Brauner et al, 2010). Moreover, several reports have described a correlation between the frequency and/or activation of NK cells with the destructiveness of the pancreatic infiltrate (Poirot et al, 2004;Feuerer et al, 2009).…”

Section: Innate Immune Cellsmentioning

confidence: 98%

Tolerance and Autoimmunity in Type 1 Diabetes

Di¹,

Giannoukakis²,

Trucco³

2011

Autoimmune Disorders - Pathogenetic Aspects

View full text Add to dashboard Cite

Distinct Phenotype and Function of NK Cells in the Pancreas of Nonobese Diabetic Mice

Abstract: Material Supplementary 8.DC1http://www.jimmunol.org/content/suppl/2010/02/01/jimmunol.080435References

Cited by 75 publications

References 52 publications

Mature natural killer cells with phenotypic and functional alterations accumulate upon sustained stimulation with IL-15/IL-15Rα complexes

Mature natural killer cells with phenotypic and functional alterations accumulate upon sustained stimulation with IL-15/IL-15Rα complexes

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

Tolerance and Autoimmunity in Type 1 Diabetes

Contact Info

Product

Resources

About