title: Deficiency in NOD antigen-presenting cell function may be responsible for suboptimal CD4+CD25+ T-cell-mediated regulation and type 1 diabetes development in NOD mice.
abstract: Various defects in antigen-presenting cells (APCs) and T-cells, including regulatory cells, have been associated with type 1 diabetes development in NOD mice. CD4(+)CD25(+) regulatory cells play a crucial role in controlling various autoimmune diseases, and a deficiency in their number or function could be involved in disease development. The current study shows that NOD mice had fewer CD4(+)CD25(+) regulatory cells, which expressed normal levels of glucocorticoid-induced tumor necrosis factor receptor and cytotoxic T-lymphocyte-associated antigen-4. We have also found that NOD CD4(+)CD25(+) cells regulate poorly in vitro after stimulation with anti-CD3 and NOD APCs in comparison with B6 CD4(+)CD25(+) cells stimulated with B6 APCs. Surprisingly, stimulation of NOD CD4(+)CD25(+) cells with B6 APCs restored regulation, whereas with the reciprocal combination, NOD APCs failed to activate B6 CD4(+)CD25(+) cells properly. Interestingly, APCs from disease-free (>30 weeks of age), but not diabetic, NOD mice were able to activate CD4(+)CD25(+) regulatory function in vitro and apparently in vivo because only spleens of disease-free NOD mice contained potent CD4(+)CD25(+) regulatory cells that prevented disease development when transferred into young NOD recipients. These data suggest that the failure of NOD APCs to activate CD4(+)CD25(+) regulatory cells may play an important role in controlling type 1 diabetes development in NOD mice.
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, 319 Abraham Flexner Way, Bldg. 55A, Rm. 405, Louisville, KY 40202, USA. p0alar01@gwise.louisville.edu
authors.forename: Pascale
authors.initials: P
authors.lastname: Alard
authors.forename: Jean N
authors.initials: JN
authors.lastname: Manirarora
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Parnell
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hudkins
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Clark
authors.forename: Michele M
authors.initials: MM
authors.lastname: Kosiewicz
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016133:Polymerase Chain Reaction; D011236:Prediabetic State / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D012333:RNA, Messenger; D015375:Receptors, Interleukin-2