In vivo apoptosis of diabetogenic T cells in NOD mice by IFN- /TNF- 

Abstract

Immunization with mycobacterial preparation such as Bacille Calmette-Guerin (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-alpha, IFN-gamma and IL-4 by splenocytes, increased the expression of Fas(high) (Apo-1/CD95), Fas ligand (FasL, CD95L) and TNF receptor (TNFR) on T cells leading to T cell apoptosis. The primary role of IFN-gamma and TNF-alpha 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-alpha 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-alpha/IFN-gamma-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.

NKT Cells Are Required for Complete Freund’s Adjuvant-Mediated Protection from Autoimmune Diabetes

“…6). As expected (21,25,53), treatment of wild-type NOD mice with CFA at 5-6 wk of age prevented the development of disease, whereas mice treated with IFA or PBS had no effect on the natural history of disease (Fig. 6A, 6B and data not shown).…”

Transforming Growth Factor-β and Natural Killer T-Cells Are Involved in the Protective Effect of a Bacterial Extract on Type 1 Diabetes

“…Note, however, that other mechanisms cannot be excluded. Thus, it has been shown that Bacille Calmette-Guerin, CFA (42), or the lymphocytic choriomeningitidis virus (43) may induce protection through IFN-␥-and TNF-␣-mediated T-cell apoptosis.…”

Reciprocity in Microbiome and Immune System Interactions and its Implications in Disease and Health

“…Of note, the protection observed after immunotherapy with mycobacterial products [66 _ 69] also depends on IFN-γ response [68] and administration of recombinant IFN-γ inhibits diabetes process in NOD mice [70]. High levels of IFN-γ and TNF-α cytokines following adjuvant immunotherapy could have a role in induction of apoptosis in diabetogenic T cells [67]. The mechanism of adjuvant effect is not restricted to IFN-γ regulation and all changes induced upon adjuvant administration might be primarily under influence of mycobacterial adjuvant-induced alterations in compostion of gut microbiota.…”