At-risk and recent-onset type 1 diabetic subjects have increased apoptosis in the CD4+CD25+high T-cell fraction

Sanja Glisic-Milosavljevic, Jill Waukau, Parthav Jailwala, Srikanta Jana, Huoy Jil Khoo, Hope Albertz, Jeffrey Woodliff, Marilyn Koppen, Ramin Alemzadeh, William Hagopian, Soumitra Ghosh

Research output: Contribution to journalArticle

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Abstract

Background. In experimental models, Type 1 diabetes (T1D) can be prevented by adoptive transfer of CD4+CD25+ (FoxP3+) suppressor or regulatory T cells. Recent studies have found a suppression defect of CD4+CD25+high T cells in human disease. In this study we measure apoptosis of CD4+CD25+high T cells to see if it could contribute to reduced suppressive activity of these cells. Methods and Findings. T-cell apoptosis was evaluated in children and adolescent (35 females/40 males) subjects comprising recent-onset and long-standing T1D subjects and their first-degree relatives, who are at variable risk to develop T1D. YOPRO1/7AAD and intracellular staining of the active form of caspase 3 were used to evaluate apoptosis. Isolated CD4+CD25+high and CD4+CD25- T cells were co-cultured in a suppression assay to assess the function of the former cells. We found that recent-onset T1D subjects show increased apoptosis of CD4+CD25+high T cells when compared to both control and long-standing T1D subjects (p<0.0001 for both groups). Subjects at high risk for developing T1D (2-3Ab+ve) show a similar trend (p<0.02 and p<0.01, respectively). On the contrary, in long-standing T1D and T2D subjects, CD4+CD25+high T cell apoptosis is at the same level as in control subjects (p = NS). Simultaneous intracellular staining of the active form of caspase 3 and FoxP3 confirmed recent-onset FoxP3+ve CD4+CD25+high T cells committed to apoptosis at a higher percentage (15.3±2.2) compared to FoxP3+ve CD4+CD25+high T cells in control subjects (6.1±1.7) (p<0.002). Compared to control subjects, both recent-onset T1D and high at-risk subjects had significantly decreased function of CD4+CD25+high T cells (p = 0.0007 and p = 0.007, respectively). Conclusions. There is a higher level of ongoing apoptosis in CD4+CD25+high T cells in recent-onset T1D subjects and in subjects at high risk for the disease. This high level of CD4+CD25+high T-cell apoptosis could be a contributing factor to markedly decreased suppressive potential of these cells in recent-onset T1D subjects.

Original languageEnglish (US)
Article numbere146
JournalPLoS ONE
Volume2
Issue number1
DOIs
StatePublished - Jan 3 2007
Externally publishedYes

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T-cells
insulin-dependent diabetes mellitus
Type 1 Diabetes Mellitus
Medical problems
apoptosis
T-lymphocytes
Apoptosis
T-Lymphocytes
caspase-3
Caspase 3
Staining and Labeling
Adoptive Transfer
Regulatory T-Lymphocytes
cells
Type 2 Diabetes Mellitus
human diseases
Theoretical Models
Assays
Cells

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Glisic-Milosavljevic, S., Waukau, J., Jailwala, P., Jana, S., Khoo, H. J., Albertz, H., ... Ghosh, S. (2007). At-risk and recent-onset type 1 diabetic subjects have increased apoptosis in the CD4+CD25+high T-cell fraction. PLoS ONE, 2(1), [e146]. https://doi.org/10.1371/journal.pone.0000146

At-risk and recent-onset type 1 diabetic subjects have increased apoptosis in the CD4+CD25+high T-cell fraction. / Glisic-Milosavljevic, Sanja; Waukau, Jill; Jailwala, Parthav; Jana, Srikanta; Khoo, Huoy Jil; Albertz, Hope; Woodliff, Jeffrey; Koppen, Marilyn; Alemzadeh, Ramin; Hagopian, William; Ghosh, Soumitra.

In: PLoS ONE, Vol. 2, No. 1, e146, 03.01.2007.

Research output: Contribution to journalArticle

Glisic-Milosavljevic, S, Waukau, J, Jailwala, P, Jana, S, Khoo, HJ, Albertz, H, Woodliff, J, Koppen, M, Alemzadeh, R, Hagopian, W & Ghosh, S 2007, 'At-risk and recent-onset type 1 diabetic subjects have increased apoptosis in the CD4+CD25+high T-cell fraction', PLoS ONE, vol. 2, no. 1, e146. https://doi.org/10.1371/journal.pone.0000146
Glisic-Milosavljevic, Sanja ; Waukau, Jill ; Jailwala, Parthav ; Jana, Srikanta ; Khoo, Huoy Jil ; Albertz, Hope ; Woodliff, Jeffrey ; Koppen, Marilyn ; Alemzadeh, Ramin ; Hagopian, William ; Ghosh, Soumitra. / At-risk and recent-onset type 1 diabetic subjects have increased apoptosis in the CD4+CD25+high T-cell fraction. In: PLoS ONE. 2007 ; Vol. 2, No. 1.
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abstract = "Background. In experimental models, Type 1 diabetes (T1D) can be prevented by adoptive transfer of CD4+CD25+ (FoxP3+) suppressor or regulatory T cells. Recent studies have found a suppression defect of CD4+CD25+high T cells in human disease. In this study we measure apoptosis of CD4+CD25+high T cells to see if it could contribute to reduced suppressive activity of these cells. Methods and Findings. T-cell apoptosis was evaluated in children and adolescent (35 females/40 males) subjects comprising recent-onset and long-standing T1D subjects and their first-degree relatives, who are at variable risk to develop T1D. YOPRO1/7AAD and intracellular staining of the active form of caspase 3 were used to evaluate apoptosis. Isolated CD4+CD25+high and CD4+CD25- T cells were co-cultured in a suppression assay to assess the function of the former cells. We found that recent-onset T1D subjects show increased apoptosis of CD4+CD25+high T cells when compared to both control and long-standing T1D subjects (p<0.0001 for both groups). Subjects at high risk for developing T1D (2-3Ab+ve) show a similar trend (p<0.02 and p<0.01, respectively). On the contrary, in long-standing T1D and T2D subjects, CD4+CD25+high T cell apoptosis is at the same level as in control subjects (p = NS). Simultaneous intracellular staining of the active form of caspase 3 and FoxP3 confirmed recent-onset FoxP3+ve CD4+CD25+high T cells committed to apoptosis at a higher percentage (15.3±2.2) compared to FoxP3+ve CD4+CD25+high T cells in control subjects (6.1±1.7) (p<0.002). Compared to control subjects, both recent-onset T1D and high at-risk subjects had significantly decreased function of CD4+CD25+high T cells (p = 0.0007 and p = 0.007, respectively). Conclusions. There is a higher level of ongoing apoptosis in CD4+CD25+high T cells in recent-onset T1D subjects and in subjects at high risk for the disease. This high level of CD4+CD25+high T-cell apoptosis could be a contributing factor to markedly decreased suppressive potential of these cells in recent-onset T1D subjects.",
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T1 - At-risk and recent-onset type 1 diabetic subjects have increased apoptosis in the CD4+CD25+high T-cell fraction

AU - Glisic-Milosavljevic, Sanja

AU - Waukau, Jill

AU - Jailwala, Parthav

AU - Jana, Srikanta

AU - Khoo, Huoy Jil

AU - Albertz, Hope

AU - Woodliff, Jeffrey

AU - Koppen, Marilyn

AU - Alemzadeh, Ramin

AU - Hagopian, William

AU - Ghosh, Soumitra

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N2 - Background. In experimental models, Type 1 diabetes (T1D) can be prevented by adoptive transfer of CD4+CD25+ (FoxP3+) suppressor or regulatory T cells. Recent studies have found a suppression defect of CD4+CD25+high T cells in human disease. In this study we measure apoptosis of CD4+CD25+high T cells to see if it could contribute to reduced suppressive activity of these cells. Methods and Findings. T-cell apoptosis was evaluated in children and adolescent (35 females/40 males) subjects comprising recent-onset and long-standing T1D subjects and their first-degree relatives, who are at variable risk to develop T1D. YOPRO1/7AAD and intracellular staining of the active form of caspase 3 were used to evaluate apoptosis. Isolated CD4+CD25+high and CD4+CD25- T cells were co-cultured in a suppression assay to assess the function of the former cells. We found that recent-onset T1D subjects show increased apoptosis of CD4+CD25+high T cells when compared to both control and long-standing T1D subjects (p<0.0001 for both groups). Subjects at high risk for developing T1D (2-3Ab+ve) show a similar trend (p<0.02 and p<0.01, respectively). On the contrary, in long-standing T1D and T2D subjects, CD4+CD25+high T cell apoptosis is at the same level as in control subjects (p = NS). Simultaneous intracellular staining of the active form of caspase 3 and FoxP3 confirmed recent-onset FoxP3+ve CD4+CD25+high T cells committed to apoptosis at a higher percentage (15.3±2.2) compared to FoxP3+ve CD4+CD25+high T cells in control subjects (6.1±1.7) (p<0.002). Compared to control subjects, both recent-onset T1D and high at-risk subjects had significantly decreased function of CD4+CD25+high T cells (p = 0.0007 and p = 0.007, respectively). Conclusions. There is a higher level of ongoing apoptosis in CD4+CD25+high T cells in recent-onset T1D subjects and in subjects at high risk for the disease. This high level of CD4+CD25+high T-cell apoptosis could be a contributing factor to markedly decreased suppressive potential of these cells in recent-onset T1D subjects.

AB - Background. In experimental models, Type 1 diabetes (T1D) can be prevented by adoptive transfer of CD4+CD25+ (FoxP3+) suppressor or regulatory T cells. Recent studies have found a suppression defect of CD4+CD25+high T cells in human disease. In this study we measure apoptosis of CD4+CD25+high T cells to see if it could contribute to reduced suppressive activity of these cells. Methods and Findings. T-cell apoptosis was evaluated in children and adolescent (35 females/40 males) subjects comprising recent-onset and long-standing T1D subjects and their first-degree relatives, who are at variable risk to develop T1D. YOPRO1/7AAD and intracellular staining of the active form of caspase 3 were used to evaluate apoptosis. Isolated CD4+CD25+high and CD4+CD25- T cells were co-cultured in a suppression assay to assess the function of the former cells. We found that recent-onset T1D subjects show increased apoptosis of CD4+CD25+high T cells when compared to both control and long-standing T1D subjects (p<0.0001 for both groups). Subjects at high risk for developing T1D (2-3Ab+ve) show a similar trend (p<0.02 and p<0.01, respectively). On the contrary, in long-standing T1D and T2D subjects, CD4+CD25+high T cell apoptosis is at the same level as in control subjects (p = NS). Simultaneous intracellular staining of the active form of caspase 3 and FoxP3 confirmed recent-onset FoxP3+ve CD4+CD25+high T cells committed to apoptosis at a higher percentage (15.3±2.2) compared to FoxP3+ve CD4+CD25+high T cells in control subjects (6.1±1.7) (p<0.002). Compared to control subjects, both recent-onset T1D and high at-risk subjects had significantly decreased function of CD4+CD25+high T cells (p = 0.0007 and p = 0.007, respectively). Conclusions. There is a higher level of ongoing apoptosis in CD4+CD25+high T cells in recent-onset T1D subjects and in subjects at high risk for the disease. This high level of CD4+CD25+high T-cell apoptosis could be a contributing factor to markedly decreased suppressive potential of these cells in recent-onset T1D subjects.

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