title: Uncoupling of proliferation and cytokines from suppression within the CD4+CD25+Foxp3+ T-cell compartment in the 1st year of human type 1 diabetes.
abstract: OBJECTIVE
  The mechanistic basis for the breakdown of T-cell tolerance in type 1 diabetes is unclear and could result from a gain of effector function and/or loss of regulatory function. In humans, the CD4+CD25+Foxp3+ T-cell compartment contains both effector and regulatory T cells, and it is not known how their relative proportions vary in disease states.
  
  
  METHODS
  We performed a longitudinal study of CD4+CD25+ T-cell function in children with type 1 diabetes at onset and throughout the 1st year of disease. Function was assessed using single-cell assays of proliferation, cytokine production, and suppression. Type 1 diabetic individuals were compared with age-matched control subjects, and suppression was directly assessed by coculture with control T-cell targets.
  
  
  RESULTS
  We identify novel functional changes within the type 1 diabetes CD4+CD25+ compartment. Type 1 diabetic CD4+CD25+ cells exhibited a striking increase in proliferative capacity in coculture with CD4 T cells that was present at onset and stable 9-12 months from diagnosis. Elevated type 1 diabetes CD4+CD25+ cell proliferation correlated with increased inflammatory cytokines interleukin 17 and tumor necrosis factor-α but not γ-interferon. Type 1 diabetes CD4+CD25+ cytokine production occurred coincident with suppression of the same cytokines in the control targets. Indeed, enhanced proliferation/cytokines by CD4+CD25+ cells was uncoupled from their suppressive ability. Longitudinally, we observed a transient defect in type 1 diabetes CD4+CD25+ suppression that unexpectedly correlated with measures of improved metabolic function.
  
  
  CONCLUSIONS
  Type 1 diabetes onset, and its subsequent remission period, is associated with two independent functional changes within the CD4+CD25+ T-cell compartment: a stable increase in effector function and a transient decrease in regulatory T-cell suppression.
authors.affiliation: David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, Rochester, New York, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Hughson
authors.forename: Irina
authors.initials: I
authors.lastname: Bromberg
authors.forename: Barbara
authors.initials: B
authors.lastname: Johnson
authors.forename: Sally
authors.initials: S
authors.lastname: Quataert
authors.forename: Nicholas
authors.initials: N
authors.lastname: Jospe
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Fowell
mesh_terms: D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D018920:Coculture Techniques; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha