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Physiological beta cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model.

Turley S, Poirot L, Hattori M, Benoist C, Mathis D - J. Exp. Med. (2003)

Bottom Line: The prelude to type-1 diabetes is leukocyte infiltration into the pancreatic islets, or insulitis.This process begins in pancreatic lymph nodes when T lymphocytes reactive to islet beta cells encounter antigen-presenting cells (APCs) displaying peptides derived from beta cell proteins.These findings have significant implications concerning the nature of the diabetes-provoking deficits in NOD mice, the identity of the primordial diabetogenic antigens, and our understanding of the balance between immunity and tolerance in a pathological context.

View Article: PubMed Central - PubMed

Affiliation: Section of Immunology and Immunogenetics, Joslin Diabetes Center and Dept. of Medicine, Brigham and Women's Hospital, Harvard Medical School, One Joslin Pl., Boston, MA 02215, USA.

ABSTRACT
The prelude to type-1 diabetes is leukocyte infiltration into the pancreatic islets, or insulitis. This process begins in pancreatic lymph nodes when T lymphocytes reactive to islet beta cells encounter antigen-presenting cells (APCs) displaying peptides derived from beta cell proteins. We show here that a ripple of physiological beta cell death, which occurs at 2 wk of age in all mouse strains, precipitates the arrival of such APCs, and that the relevant APC is a dendritic cell of CD11c+CD11b+CD8alpha- phenotype. These findings have significant implications concerning the nature of the diabetes-provoking deficits in NOD mice, the identity of the primordial diabetogenic antigens, and our understanding of the balance between immunity and tolerance in a pathological context.

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The presence of dead β cells provokes activation of naive BDC2.5 T cells in neonatal PLNs. (a) Activation of transferred naive BDC2.5 T cells (gated on CD4+Vβ4+ cells) in PLNs and ILNs after intrapancreatic implantation of dead islets or buffer into 6-d-old NOD mice. Proliferation was assessed in all experiments ∼66 h after transfer by CFSE dilution in CD4+ T cells. (b) Activation of transferred naive BDC2.5 T cells (gated on CD4+Vβ4+ cells) in PLNs after intraperitoneal injection of STZ into 6-d-old NOD mice.
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fig5: The presence of dead β cells provokes activation of naive BDC2.5 T cells in neonatal PLNs. (a) Activation of transferred naive BDC2.5 T cells (gated on CD4+Vβ4+ cells) in PLNs and ILNs after intrapancreatic implantation of dead islets or buffer into 6-d-old NOD mice. Proliferation was assessed in all experiments ∼66 h after transfer by CFSE dilution in CD4+ T cells. (b) Activation of transferred naive BDC2.5 T cells (gated on CD4+Vβ4+ cells) in PLNs after intraperitoneal injection of STZ into 6-d-old NOD mice.

Mentions: We tested this notion with different strategies using the BDC2.5 TCR tg system. The still-unidentified antigen recognized by BDC2.5 T cells appears to be associated with particulate fractions of β cells, possibly on the cytoplasmic face of secretory granules (22). Although the BDC2.5 antigen is known to be synthesized shortly after birth (10), its subcellular localization suggests that it might be more likely encountered when the integrity of the β cell membrane is disrupted, for example, during programmed cell death or cell injury. To assess this possibility, we transferred CFSE-labeled naive BDC2.5 T cells into 6-d-old NOD mice that were unmanipulated or had been intrapancreatically implanted with dead islets. The activation of these transferred cells and their proliferation in draining and distal LNs was ascertained by flow cytometry 66 h after transfer, as a dilution of the CFSE label with each cell division. In the latter case, a much higher fraction (47 vs. 3%) of the transferred T cells was activated and proliferated in the PLNs, a clear response to dying β cells (Fig. 5 a). The intrapancreatic injection of buffer alone resulted in a small increase in BDC2.5 T cell activation (3 vs. 13%) in PLNs, suggesting that the surgical procedure may have caused some β cell death (Fig. 5 a). Transferred BDC2.5 T cells remained naive in ILNs in all recipients (Fig. 5 a). We also transferred CFSE-labeled naive BDC2.5 T cells into 6-d-old recipients that had or had not been treated with STZ, a cytotoxic drug to which β cells are particularly sensitive. A single injection of STZ resulted in a much more robust PLN activation (64 vs. 2%) of the transferred T cells (Fig. 5 b). These results indicate that β cell death within the pancreas is capable of provoking priming of islet-reactive CD4+ T cells circulating through PLNs before 10 d of age.


Physiological beta cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model.

Turley S, Poirot L, Hattori M, Benoist C, Mathis D - J. Exp. Med. (2003)

The presence of dead β cells provokes activation of naive BDC2.5 T cells in neonatal PLNs. (a) Activation of transferred naive BDC2.5 T cells (gated on CD4+Vβ4+ cells) in PLNs and ILNs after intrapancreatic implantation of dead islets or buffer into 6-d-old NOD mice. Proliferation was assessed in all experiments ∼66 h after transfer by CFSE dilution in CD4+ T cells. (b) Activation of transferred naive BDC2.5 T cells (gated on CD4+Vβ4+ cells) in PLNs after intraperitoneal injection of STZ into 6-d-old NOD mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2194112&req=5

fig5: The presence of dead β cells provokes activation of naive BDC2.5 T cells in neonatal PLNs. (a) Activation of transferred naive BDC2.5 T cells (gated on CD4+Vβ4+ cells) in PLNs and ILNs after intrapancreatic implantation of dead islets or buffer into 6-d-old NOD mice. Proliferation was assessed in all experiments ∼66 h after transfer by CFSE dilution in CD4+ T cells. (b) Activation of transferred naive BDC2.5 T cells (gated on CD4+Vβ4+ cells) in PLNs after intraperitoneal injection of STZ into 6-d-old NOD mice.
Mentions: We tested this notion with different strategies using the BDC2.5 TCR tg system. The still-unidentified antigen recognized by BDC2.5 T cells appears to be associated with particulate fractions of β cells, possibly on the cytoplasmic face of secretory granules (22). Although the BDC2.5 antigen is known to be synthesized shortly after birth (10), its subcellular localization suggests that it might be more likely encountered when the integrity of the β cell membrane is disrupted, for example, during programmed cell death or cell injury. To assess this possibility, we transferred CFSE-labeled naive BDC2.5 T cells into 6-d-old NOD mice that were unmanipulated or had been intrapancreatically implanted with dead islets. The activation of these transferred cells and their proliferation in draining and distal LNs was ascertained by flow cytometry 66 h after transfer, as a dilution of the CFSE label with each cell division. In the latter case, a much higher fraction (47 vs. 3%) of the transferred T cells was activated and proliferated in the PLNs, a clear response to dying β cells (Fig. 5 a). The intrapancreatic injection of buffer alone resulted in a small increase in BDC2.5 T cell activation (3 vs. 13%) in PLNs, suggesting that the surgical procedure may have caused some β cell death (Fig. 5 a). Transferred BDC2.5 T cells remained naive in ILNs in all recipients (Fig. 5 a). We also transferred CFSE-labeled naive BDC2.5 T cells into 6-d-old recipients that had or had not been treated with STZ, a cytotoxic drug to which β cells are particularly sensitive. A single injection of STZ resulted in a much more robust PLN activation (64 vs. 2%) of the transferred T cells (Fig. 5 b). These results indicate that β cell death within the pancreas is capable of provoking priming of islet-reactive CD4+ T cells circulating through PLNs before 10 d of age.

Bottom Line: The prelude to type-1 diabetes is leukocyte infiltration into the pancreatic islets, or insulitis.This process begins in pancreatic lymph nodes when T lymphocytes reactive to islet beta cells encounter antigen-presenting cells (APCs) displaying peptides derived from beta cell proteins.These findings have significant implications concerning the nature of the diabetes-provoking deficits in NOD mice, the identity of the primordial diabetogenic antigens, and our understanding of the balance between immunity and tolerance in a pathological context.

View Article: PubMed Central - PubMed

Affiliation: Section of Immunology and Immunogenetics, Joslin Diabetes Center and Dept. of Medicine, Brigham and Women's Hospital, Harvard Medical School, One Joslin Pl., Boston, MA 02215, USA.

ABSTRACT
The prelude to type-1 diabetes is leukocyte infiltration into the pancreatic islets, or insulitis. This process begins in pancreatic lymph nodes when T lymphocytes reactive to islet beta cells encounter antigen-presenting cells (APCs) displaying peptides derived from beta cell proteins. We show here that a ripple of physiological beta cell death, which occurs at 2 wk of age in all mouse strains, precipitates the arrival of such APCs, and that the relevant APC is a dendritic cell of CD11c+CD11b+CD8alpha- phenotype. These findings have significant implications concerning the nature of the diabetes-provoking deficits in NOD mice, the identity of the primordial diabetogenic antigens, and our understanding of the balance between immunity and tolerance in a pathological context.

Show MeSH
Related in: MedlinePlus