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CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion.

Herman AE, Freeman GJ, Mathis D, Benoist C - J. Exp. Med. (2004)

Bottom Line: Here, we report that Tregs and T effector cells (Teffs) coexist within the pancreatic lesion before type 1 diabetes onset.We find that BDC2.5 T cell receptor transgenic animals contain a small subset of FoxP3 positive CD4+CD25+CD69- cells in the pancreas, actively turning over, expressing the clonotypic receptor, and containing functional regulatory activity.Blockade of ICOS rapidly converts early insulitis to diabetes, which disrupts the balance of Teffs and Tregs and promotes a very broad shift in the expression of the T regulatory-specific profile.

View Article: PubMed Central - PubMed

Affiliation: Section on Immunology and Immunogenetics, Joslin Diabetes Center, Boston, MA 02215, USA.

ABSTRACT
CD4+CD25+ T regulatory cells (Tregs) prevent autoimmune disease, yet little is known about precisely where they exert their influence naturally in a spontaneous autoimmune disorder. Here, we report that Tregs and T effector cells (Teffs) coexist within the pancreatic lesion before type 1 diabetes onset. We find that BDC2.5 T cell receptor transgenic animals contain a small subset of FoxP3 positive CD4+CD25+CD69- cells in the pancreas, actively turning over, expressing the clonotypic receptor, and containing functional regulatory activity. Gene expression profiling confirms that the CD4+CD25+CD69- cells in pancreatic tissue express transcripts diagnostic of regulatory cells, but with significantly higher levels of interleukin 10 and inducible costimulator (ICOS) than their lymph node counterparts. Blockade of ICOS rapidly converts early insulitis to diabetes, which disrupts the balance of Teffs and Tregs and promotes a very broad shift in the expression of the T regulatory-specific profile. Thus, CD4+CD25+69- Tregs operate directly in the autoimmune lesion and are dependent on ICOS to keep it in a nondestructive state.

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CD4+CD25+CD69−, CD25loCD69+, and CD25−CD69− subsets are proliferating in the pancreas and LNs of unmanipulated BDC2.5 mice. 3–4-wk-old BDC2.5 mice were fed BrdU in their drinking water for 5 d. Pancreas (Panc), pancreatic LNs (PLN), or inguinal LN (ILN) were isolated and analyzed by five-color flow cytometry for CD4, B220, CD25, CD69, and BrdU expression. Cells were gated for lymphocytes, CD4+B220− cells, and indicated CD25/CD69 subsets (as in Fig. 1 B). Isotype control (thick line) versus BrdU (thin line) staining is shown. Data are representative of three experiments.
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fig2: CD4+CD25+CD69−, CD25loCD69+, and CD25−CD69− subsets are proliferating in the pancreas and LNs of unmanipulated BDC2.5 mice. 3–4-wk-old BDC2.5 mice were fed BrdU in their drinking water for 5 d. Pancreas (Panc), pancreatic LNs (PLN), or inguinal LN (ILN) were isolated and analyzed by five-color flow cytometry for CD4, B220, CD25, CD69, and BrdU expression. Cells were gated for lymphocytes, CD4+B220− cells, and indicated CD25/CD69 subsets (as in Fig. 1 B). Isotype control (thick line) versus BrdU (thin line) staining is shown. Data are representative of three experiments.

Mentions: An interesting issue was whether the T cells were actively proliferating in the pancreatic lesion because previous analyses of Treg proliferation have shown expansion in the draining node or in the intestine of lymphopenic hosts (30), but not the target tissue of autoimmunity in mice with a full lymphoid compartment. Flow cytometric analysis of mice fed with BrdU for 5 d showed that all CD4+ cell phenotypes in the pancreatic lesion proliferated (Fig. 2). If anything, CD25+ CD69− cells were the most active. This was also the case in the draining PLN, but not in the irrelevant ILN. Thus, the insulitic lesion is not inert, and cells with both regulatory and effector phenotypes are turning over rapidly in the presence of a full lymphoid compartment.


CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion.

Herman AE, Freeman GJ, Mathis D, Benoist C - J. Exp. Med. (2004)

CD4+CD25+CD69−, CD25loCD69+, and CD25−CD69− subsets are proliferating in the pancreas and LNs of unmanipulated BDC2.5 mice. 3–4-wk-old BDC2.5 mice were fed BrdU in their drinking water for 5 d. Pancreas (Panc), pancreatic LNs (PLN), or inguinal LN (ILN) were isolated and analyzed by five-color flow cytometry for CD4, B220, CD25, CD69, and BrdU expression. Cells were gated for lymphocytes, CD4+B220− cells, and indicated CD25/CD69 subsets (as in Fig. 1 B). Isotype control (thick line) versus BrdU (thin line) staining is shown. Data are representative of three experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211778&req=5

fig2: CD4+CD25+CD69−, CD25loCD69+, and CD25−CD69− subsets are proliferating in the pancreas and LNs of unmanipulated BDC2.5 mice. 3–4-wk-old BDC2.5 mice were fed BrdU in their drinking water for 5 d. Pancreas (Panc), pancreatic LNs (PLN), or inguinal LN (ILN) were isolated and analyzed by five-color flow cytometry for CD4, B220, CD25, CD69, and BrdU expression. Cells were gated for lymphocytes, CD4+B220− cells, and indicated CD25/CD69 subsets (as in Fig. 1 B). Isotype control (thick line) versus BrdU (thin line) staining is shown. Data are representative of three experiments.
Mentions: An interesting issue was whether the T cells were actively proliferating in the pancreatic lesion because previous analyses of Treg proliferation have shown expansion in the draining node or in the intestine of lymphopenic hosts (30), but not the target tissue of autoimmunity in mice with a full lymphoid compartment. Flow cytometric analysis of mice fed with BrdU for 5 d showed that all CD4+ cell phenotypes in the pancreatic lesion proliferated (Fig. 2). If anything, CD25+ CD69− cells were the most active. This was also the case in the draining PLN, but not in the irrelevant ILN. Thus, the insulitic lesion is not inert, and cells with both regulatory and effector phenotypes are turning over rapidly in the presence of a full lymphoid compartment.

Bottom Line: Here, we report that Tregs and T effector cells (Teffs) coexist within the pancreatic lesion before type 1 diabetes onset.We find that BDC2.5 T cell receptor transgenic animals contain a small subset of FoxP3 positive CD4+CD25+CD69- cells in the pancreas, actively turning over, expressing the clonotypic receptor, and containing functional regulatory activity.Blockade of ICOS rapidly converts early insulitis to diabetes, which disrupts the balance of Teffs and Tregs and promotes a very broad shift in the expression of the T regulatory-specific profile.

View Article: PubMed Central - PubMed

Affiliation: Section on Immunology and Immunogenetics, Joslin Diabetes Center, Boston, MA 02215, USA.

ABSTRACT
CD4+CD25+ T regulatory cells (Tregs) prevent autoimmune disease, yet little is known about precisely where they exert their influence naturally in a spontaneous autoimmune disorder. Here, we report that Tregs and T effector cells (Teffs) coexist within the pancreatic lesion before type 1 diabetes onset. We find that BDC2.5 T cell receptor transgenic animals contain a small subset of FoxP3 positive CD4+CD25+CD69- cells in the pancreas, actively turning over, expressing the clonotypic receptor, and containing functional regulatory activity. Gene expression profiling confirms that the CD4+CD25+CD69- cells in pancreatic tissue express transcripts diagnostic of regulatory cells, but with significantly higher levels of interleukin 10 and inducible costimulator (ICOS) than their lymph node counterparts. Blockade of ICOS rapidly converts early insulitis to diabetes, which disrupts the balance of Teffs and Tregs and promotes a very broad shift in the expression of the T regulatory-specific profile. Thus, CD4+CD25+69- Tregs operate directly in the autoimmune lesion and are dependent on ICOS to keep it in a nondestructive state.

Show MeSH
Related in: MedlinePlus