Interferon-gamma receptor signaling is dispensable in the development of autoimmune type 1 diabetes in NOD mice.
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)-gamma or the alpha-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 beta-chain signaling (located on chromosome 16) rather than the alpha-chain ligand binding domain (located on chromosome 10) of the IFN-gamma receptor. These NOD.IFNgammaRBnull 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 Thl cytokine IFN-gamma and having T-cells that produce greatly enhanced levels of IL-4, NOD.IFNgammaRBnull 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-gamma receptor alpha-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-gamma and a concurrent shift to greatly enhanced Th2 cytokine production. This finding calls into question whether clinical protocols designed to shift beta-cell autoreactive T-cells from a Thl to Th2 cytokine production profile will truly be safe and efficacious in blocking the development of type 1 diabetes in humans.
Serreze
D V
DV
Jackson Laboratory, Bar Harbor, Maine 04609, USA. dvs@jax.org
Post
C M
CM
Chapman
H D
HD
Johnson
E A
EA
Lu
B
B
Rothman
P B
PB
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D018014:Gene Transfer Techniques; D020022:Genetic Predisposition to Disease; D015847:Interleukin-4 / Q000096:biosynthesis; D007962:Leukocytes / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics; D017471:Receptors, Interferon / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D018418:Th2 Cells / Q000378:metabolism; D000096743:Interferon gamma Receptor
D015847:Interleukin-4; D020033:Protein Isoforms; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor