title: At-risk and recent-onset type 1 diabetic subjects have increased apoptosis in the CD4+CD25+ T-cell fraction.
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.
  
  
  RESULTS
  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.
authors.affiliation: The Max McGee National Center for Juvenile Diabetes and Human Molecular Genetics Center, Medical College of Wisconsin and the Children's Research Institute of the Children's Hospital of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Sanja
authors.initials: S
authors.lastname: Glisic-Milosavljevic
authors.forename: Jill
authors.initials: J
authors.lastname: Waukau
authors.forename: Parthav
authors.initials: P
authors.lastname: Jailwala
authors.forename: Srikanta
authors.initials: S
authors.lastname: Jana
authors.forename: Huoy-Jii
authors.initials: HJ
authors.lastname: Khoo
authors.forename: Hope
authors.initials: H
authors.lastname: Albertz
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Woodliff
authors.forename: Marilyn
authors.initials: M
authors.lastname: Koppen
authors.forename: Ramin
authors.initials: R
authors.lastname: Alemzadeh
authors.forename: William
authors.initials: W
authors.lastname: Hagopian
authors.forename: Soumitra
authors.initials: S
authors.lastname: Ghosh
mesh_terms: D000293:Adolescent; D017209:Apoptosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008297:Male; D012307:Risk Factors; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit