International Immunology Advance Access originally published online on May 4, 2006
International Immunology 2006 18(7):1001-1015; doi:10.1093/intimm/dxl035
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A novel mechanism of regulatory T cell-mediated down-regulation of autoimmunity
1 Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, N6A 5C1, Canada
2 Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
3 Robarts Research Institute, London, Ontario, Canada
4 Institute of Infection and Immunity, Canadian Institutes of Health Research, London, Ontario, Canada
Correspondence to: B. Singh; E-mail: bsingh{at}uwo.ca
We have established a novel CD4 and CD8 double-positive CD25+ T regulatory (Treg) clone, MT-5B, from lymph nodes of type 1 diabetes prone non-obese diabetic (NOD) mice immunized with CFA. CFA has previously been shown to prevent the onset of diabetes by inducing Treg cells. In vitro, clone MT-5B was anergic to a panel of antigen stimulations and exerted an immunosuppressive effect in antigen-non-specific and cell contact-independent manners. In vivo, clone MT-5B blocked the adoptive transfer of diabetes. Proteomics and immunoadsorption studies identified the suppressive proteins secreted by clone MT-5B as granzyme B (GrB) and perforin (PFN). GrB-mediated immune suppression was PFN dependent. Removal of GrB or PFN from the culture supernatant (SN) of MT-5B cells or pre-incubation of MT-5B cells with ethyleneglycol-bis(aminoethylether)-tetraacetic acid which blocks PFN activity reduced the immunosuppressive effect in vitro. Pre-incubation of diabetogenic splenocytes from NOD mice with MT-5B SN impaired their ability to transfer disease by inducing T cell apoptosis, and removal of GrB from MT-5B SN by immunoadsorption decreased the effector function of MT-5B SN on diabetogenic splenocytes. Immunization of NOD mice with CFA increased the expression of GrB+ CD4 T cells, indicating that these cells are present in vivo. In conclusion, we describe a novel mechanism of cell contact-independent immune suppression in which Treg cells maintain immune homeostasis by secreting GrB/PFN.
Keywords: autoimmunity, CFA, diabetes, granzyme B/perforin, regulatory T cells
Transmitting editor: C. J. Paige
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