International Immunology Advance Access originally published online on October 18, 2004
International Immunology 2004 16(12):1723-1732; doi:10.1093/intimm/dxh173
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© 2004 The Japanese Society for Immunology
In vivo apoptosis of diabetogenic T cells in NOD mice by IFN-
/TNF-
1 Department of Microbiology and Immunology, University of Western Ontario, 2 Robarts Research Institute and 3 Canadian Institutes of Health Research, Institute of Infection & Immunity, London, Ontario, Canada
Correspondence to: B. Singh; E-mail: bsingh{at}uwo.ca
Immunization with mycobacterial preparation such as Bacille Calmette–Guérin (BCG) or complete Freund's adjuvant (CFA) prevents the onset and recurrence of type 1 diabetes in non-obese diabetic (NOD) mice. In this study, we explored the mechanism underlying the down-regulation of diabetogenic T cells by BCG treatment. We found that the potential of splenocytes from BCG-immunized diabetic NOD mice to adoptively transfer diabetes was significantly impaired. BCG immunization sequentially induced the production of TNF-
, IFN-
and IL-4 by splenocytes, increased the expression of Fashigh (Apo-1/CD95), Fas ligand (FasL, CD95L) and TNF receptor (TNFR) on T cells leading to T cell apoptosis. The primary role of IFN- and TNF- in BCG-immunotherapy was demonstrated by (i) reversing the immune regulatory effect of BCG by in vivo treatment with neutralizing anti-cytokine antibodies, (ii) inducing effect similar to BCG by treatment with these cytokines. We show that Fas and TNF are two pathways in BCG-induced apoptosis of diabetogenic T cells, since in vitro blocking FasL or TNFR1 with antibody reduced T cell apoptosis and increased T cell proliferative response. In addition, TNF- and agonistic anti-Fas antibody had a synergistic effect on the in vitro apoptosis of diabetogenic T cells. Our results suggest that BCG down-regulates destructive autoimmunity by TNF-/IFN--induced apoptosis of diabetogenic T cells through both Fas and TNF pathways. These studies provide a novel mechanism for blocking disease recurrence and immune modulating effect of BCG immunization in type 1 diabetes.
Keywords: apoptosis, BCG, cytokines, immunoregulation, mycobacterium, NOD mice, type 1 diabetes
Transmitting editor: C. J. Paige
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