title: Regulatory function of a novel population of mouse autoantigen-specific Foxp3 regulatory T cells depends on IFN-gamma, NO, and contact with target cells.
abstract: BACKGROUND
  Both naturally arising Foxp3(+) and antigen-induced Foxp3(-) regulatory T cells (Treg) play a critical role in regulating immune responses, as well as in preventing autoimmune diseases and graft rejection. It is known that antigen-specific Treg are more potent than polyclonal Treg in suppressing pathogenic immune responses that cause autoimmunity and inflammation. However, difficulty in identifying and isolating a sufficient number of antigen-specific Treg has limited their use in research to elucidate the mechanisms underlying their regulatory function and their potential role in therapy.
  
  
  RESULTS
  Using a novel class II MHC tetramer, we have isolated a population of CD4(+) Foxp3(-) T cells specific for the autoantigen glutamic acid decarboxylase p286-300 peptide (NR286 T cells) from diabetes-resistant non-obese resistant (NOR) mice. These Foxp3(-) NR286 T cells functioned as Treg that were able to suppress target T cell proliferation in vitro and inhibit type 1 diabetes in animals. Unexpected results from mechanistic studies in vitro showed that their regulatory function was dependent on not only IFN-gamma and nitric oxide, but also on cell contact with target cells. In addition, separating NR286 Treg from target T cells in transwell assays abolished both production of NO and suppression of target T cells, regardless of whether IFN-gamma was produced in cell cultures. Therefore, production of NO, not IFN-gamma, was cell contact dependent, suggesting that NO may function downstream of IFN-gamma in mediating regulatory function of NR286 Treg.
  
  
  CONCLUSIONS
  These studies identified a unique population of autoantigen-specific Foxp3(-) Treg that can exert their regulatory function dependent on not only IFN-gamma and NO but also cell contact with target cells.
authors.affiliation: Department of Immunology, Beckman Research Institute, City of Hope, Duarte, California, USA.
authors.forename: Cyndi
authors.initials: C
authors.lastname: Chen
authors.forename: Chih-Pin
authors.initials: CP
authors.lastname: Liu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000737:chemistry*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D009569:Nitric Oxide / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism
chemical_list: D001324:Autoantigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D000949:Histocompatibility Antigens Class II; D016753:Interleukin-10; D009569:Nitric Oxide; D007371:Interferon-gamma