There have been two previous conflicting reports that the development of T-cell-mediated autoimmune diabetes (type 1 diabetes) was respectively unaffected or inhibited in NOD mice genetically deficient in the T-helper (Th) 1 cytokine interferon (IFN)-γ or the α-chain subunit of its receptor. Our goal was to resolve this conundrum by congenically transferring, from a 129 donor strain to the NOD background, a functionally inactivated gene for the β-chain signaling (located on chromosome 16) rather than the α-chain ligand binding domain (located on chromosome 10) of the IFN-γ receptor. These NOD.IFNγRB(null) mice were characterized by normal patterns of leukocyte development and T-cells that produced greatly enhanced levels of the putatively type 1 diabetes-protective Th2 cytokine interleukin (IL)-4. However, despite being unable to respond to the primary Th1 cytokine IFN-γ and having T-cells that produce greatly enhanced levels of IL-4, NOD.IFNγRB(null) mice remained highly susceptible to type 1 diabetes. This result indicated that the previously reported inhibition of type 1 diabetes in NOD mice carrying a functionally inactivated IFN-γ receptor α-chain gene may have been due to a closely linked and previously unidentified diabetes resistance allele. Furthermore, our results indicate that the pathogenicity of diabetogenic T-cells in NOD mice is not dampened by an inability to respond to IFN-γ and a concurrent shift to greatly enhanced Th2 cytokine production. This finding calls into question whether clinical protocols designed to shift β-cell autoreactive T-cells from a Th1 to Th2 cytokine production profile will truly be safe and efficacious in blocking the development of type 1 diabetes in humans.
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism