Limits...
The expression of the beta cell-derived autoimmune ligand for the killer receptor nkp46 is attenuated in type 2 diabetes.

Gur C, Enk J, Weitman E, Bachar E, Suissa Y, Cohen G, Schyr RB, Sabanay H, Horwitz E, Glaser B, Dor Y, Pribluda A, Hanna JH, Leibowitz G, Mandelboim O - PLoS ONE (2013)

Bottom Line: Following glucose stimulation the NKp46 ligand translocates to the cell membrane and its secretion decreases.We further demonstrate by using several modalities that the unknown NKp46 ligand is not insulin.We demonstrate that the expression of the NKp46 ligand is decreased in all models of T2D studied, suggesting that NKp46 is not involved in T2D.

View Article: PubMed Central - PubMed

Affiliation: The Lautenberg Center for General and Tumor Immunology, The Department of Immunology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.

ABSTRACT
NK cells rapidly kill tumor cells, virus infected cells and even self cells. This is mediated via killer receptors, among which NKp46 (NCR1 in mice) is prominent. We have recently demonstrated that in type 1 diabetes (T1D) NK cells accumulate in the diseased pancreas and that they manifest a hyporesponsive phenotype. In addition, we found that NKp46 recognizes an unknown ligand expressed by beta cells derived from humans and mice and that blocking of NKp46 activity prevented diabetes development. Here we investigated the properties of the unknown NKp46 ligand. We show that the NKp46 ligand is mainly located in insulin granules and that it is constitutively secreted. Following glucose stimulation the NKp46 ligand translocates to the cell membrane and its secretion decreases. We further demonstrate by using several modalities that the unknown NKp46 ligand is not insulin. Finally, we studied the expression of the NKp46 ligand in type 2 diabetes (T2D) using 3 different in vivo models and 2 species; mice and gerbils. We demonstrate that the expression of the NKp46 ligand is decreased in all models of T2D studied, suggesting that NKp46 is not involved in T2D.

Show MeSH

Related in: MedlinePlus

Insulinoma staining.(A-B) Immunofluorescence images of INS-1E (A) and MIN6 (B) beta cell lines. Left images represent staining with anti-insulin antibody (Insulin, red), middle images represent staining with the NKp46-Ig (NKp46 ligand, green) and the right images represent the merge signal (Merge, yellow). Arrows indicate areas positive for NKp46-Ig staining and negative for insulin. Representative of three independent staining is shown. Magnificationx1800, scale bar-10 µm.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3757008&req=5

pone-0074033-g002: Insulinoma staining.(A-B) Immunofluorescence images of INS-1E (A) and MIN6 (B) beta cell lines. Left images represent staining with anti-insulin antibody (Insulin, red), middle images represent staining with the NKp46-Ig (NKp46 ligand, green) and the right images represent the merge signal (Merge, yellow). Arrows indicate areas positive for NKp46-Ig staining and negative for insulin. Representative of three independent staining is shown. Magnificationx1800, scale bar-10 µm.

Mentions: To further characterize the regulation of NKp46 ligand expression we stained the insulinoma cell lines INS-1E and MIN6 with anti-insulin and with NKp46-Ig (Figure 2, red and green respectively). As can be seen in Figure 2, insulin co-locolized with NKp46-Ig in both cells, however, green dots (indicative for NKp46-Ig staining only, some are marked by arrows) were clearly seen in the merge pictures, suggesting that the NKp46 ligand is not insulin. No staining was observed when the control CD16-Ig fusion protein was used (Figure S1A).


The expression of the beta cell-derived autoimmune ligand for the killer receptor nkp46 is attenuated in type 2 diabetes.

Gur C, Enk J, Weitman E, Bachar E, Suissa Y, Cohen G, Schyr RB, Sabanay H, Horwitz E, Glaser B, Dor Y, Pribluda A, Hanna JH, Leibowitz G, Mandelboim O - PLoS ONE (2013)

Insulinoma staining.(A-B) Immunofluorescence images of INS-1E (A) and MIN6 (B) beta cell lines. Left images represent staining with anti-insulin antibody (Insulin, red), middle images represent staining with the NKp46-Ig (NKp46 ligand, green) and the right images represent the merge signal (Merge, yellow). Arrows indicate areas positive for NKp46-Ig staining and negative for insulin. Representative of three independent staining is shown. Magnificationx1800, scale bar-10 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3757008&req=5

pone-0074033-g002: Insulinoma staining.(A-B) Immunofluorescence images of INS-1E (A) and MIN6 (B) beta cell lines. Left images represent staining with anti-insulin antibody (Insulin, red), middle images represent staining with the NKp46-Ig (NKp46 ligand, green) and the right images represent the merge signal (Merge, yellow). Arrows indicate areas positive for NKp46-Ig staining and negative for insulin. Representative of three independent staining is shown. Magnificationx1800, scale bar-10 µm.
Mentions: To further characterize the regulation of NKp46 ligand expression we stained the insulinoma cell lines INS-1E and MIN6 with anti-insulin and with NKp46-Ig (Figure 2, red and green respectively). As can be seen in Figure 2, insulin co-locolized with NKp46-Ig in both cells, however, green dots (indicative for NKp46-Ig staining only, some are marked by arrows) were clearly seen in the merge pictures, suggesting that the NKp46 ligand is not insulin. No staining was observed when the control CD16-Ig fusion protein was used (Figure S1A).

Bottom Line: Following glucose stimulation the NKp46 ligand translocates to the cell membrane and its secretion decreases.We further demonstrate by using several modalities that the unknown NKp46 ligand is not insulin.We demonstrate that the expression of the NKp46 ligand is decreased in all models of T2D studied, suggesting that NKp46 is not involved in T2D.

View Article: PubMed Central - PubMed

Affiliation: The Lautenberg Center for General and Tumor Immunology, The Department of Immunology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.

ABSTRACT
NK cells rapidly kill tumor cells, virus infected cells and even self cells. This is mediated via killer receptors, among which NKp46 (NCR1 in mice) is prominent. We have recently demonstrated that in type 1 diabetes (T1D) NK cells accumulate in the diseased pancreas and that they manifest a hyporesponsive phenotype. In addition, we found that NKp46 recognizes an unknown ligand expressed by beta cells derived from humans and mice and that blocking of NKp46 activity prevented diabetes development. Here we investigated the properties of the unknown NKp46 ligand. We show that the NKp46 ligand is mainly located in insulin granules and that it is constitutively secreted. Following glucose stimulation the NKp46 ligand translocates to the cell membrane and its secretion decreases. We further demonstrate by using several modalities that the unknown NKp46 ligand is not insulin. Finally, we studied the expression of the NKp46 ligand in type 2 diabetes (T2D) using 3 different in vivo models and 2 species; mice and gerbils. We demonstrate that the expression of the NKp46 ligand is decreased in all models of T2D studied, suggesting that NKp46 is not involved in T2D.

Show MeSH
Related in: MedlinePlus