Interferon-γ Is Essential for Destruction of β Cells and Development of Insulin-dependent Diabetes Mellitus

Autoimmune mediated destruction of β cells of the islets of Langerhans leads to insulin-dependent diabetes mellitus (IDDM). Rat insulin promoter (RIP) lymphocytic choriomeningitis virus (LCMV) transgenic mice that express the nucleoprotein (NP) or glycoprotein (GP) of LCMV under control of the RIP in their β cells develop IDDM after infection with LCMV and serve as a model for virus-induced IDDM. Recently, Kagi et al. (Kagi, D., B. Odermatt, P. Ohashi, R.M. Zinkernagel, and H. Hengartner. 1996. J. Exp. Med. 183:2143–2149) showed, using RIP LCMV perforin-deficient mice, that IDDM does not occur in the absence of perforin. They concluded that perforin-mediated killing by cytotoxic T lymphocytes (CTLs) is the main factor needed for β cell injury and destruction. Here we provide evidence that killing of β cells is more complex and multifactorial. By the use of our RIP LCMV model, we show that in perforin competent but interferon-γ (IFN-γ)–deficient mice, β cell injury is limited and IDDM does not occur. For these studies, double transgenic mice were generated that were genetically deficient in the production of IFN-γ and express LCMV NP or GP in their β cells. In such mice, IDDM was ab