Stat4-null non-obese diabetic mice: protection from diabetes and experimental allergic encephalomyelitis, but with concomitant epitope spread

Abstract

There is much interest in therapeutic manipulation of cytokine responses in autoimmunity, yet studies in mouse models have sometimes produced conflicting findings as to the role of particular mediators in disease. Examples include the contradictory findings regarding susceptibility to experimental allergic encephalomyelitis (EAE) or diabetes in knockout mice for various individual Th1 or Th2 cytokines or their receptors. An alternative approach to the analysis of Th1 and Th2 mechanisms in these diseases is to investigate strains carrying a null mutation for molecules involved in cytokine receptor signal transduction, signal transducer and activator of transcription (Stat4) and Stat6. Stat4 is pivotal in Th1 polarization, being activated when IL-12 binds the IL-12R and leading to the production of IFNgamma. We here report disease susceptibility in non-obese diabetic mice carrying a Stat4-null mutation. Knockout mice were almost completely protected from diabetes, only rarely showing pancreatic peri-islet infiltrates. Furthermore, there was near complete protection from the induction of EAE by either of the two encephalitogenic myelin epitopes. Despite this protection, Stat4-null mice showed clear epitope spread compared with controls during myelin oligodendrocyte glycoprotein-induced EAE as judged by T cell proliferation, although this was not associated with a strong Th1 response to the initial or spread epitope and, furthermore, there was no evidence of a switch to Th2 cytokines.

CD4+ T‐cell‐mediated anti‐tumor immunity can be uncoupled from autoimmunity via the STAT4/STAT6 signaling axis

“…The detection of IFN-g in the Stat4 À/À mice suggests that vaccination with AdhDCT may activate other signaling pathways that bypass STAT4-dependent production of IFN-g [26][27][28]. Nevertheless, we believe that our data are consistent with a role of STAT4 signaling downstream of the effector CD4 1 T cells as seen in a diabetes adoptive transfer model where diabetogenic CD4 1 T cells failed to produce disease in Stat4 À/À hosts [29]. If our hypothesis is proven to be correct, then targeting of STAT4 with specific inhibitors may provide a useful tool for suppressing autoimmune sequelae following cancer immunotherapy using CD4 1 T-celldependent strategies.…”

Modelling MS: Chronic-Relapsing EAE in the NOD/Lt Mouse Strain

“…Stat4 regulation of Th1 polarization was confirmed by Boyton et al (2005) using a Stat4-null mutant in the NOD/Lt background. Stat4-null mice were almost completely protected from EAE, but none exhibited epitope spread with MOG .…”

A meta-analysis of the association of STAT4 polymorphism with systemic lupus erythematosus

“…The same allele (rs7574865) has been reported to be associated with multiple autoimmune diseases, such as SLE, rheumatoid arthritis, type 1 diabetes, Sjogren's syndrome, Wegener's granulomatosis, and Crohn's disease [3,[24][25][26][27]. Moreover, some studies have showed that STAT4-deficient mice were resistant to animal models of diabetes, experimental autoimmune encephalomyelitis (EAE), and arthritis [28,29]. These results strongly indicate that STAT4 might be a common genetic risk factor for autoimmune diseases.…”