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Accession IconGSE12389

Interferon--dependent regulatory circuits in immune inflammation highlighted in diabetes

Organism Icon Mus musculus
Sample Icon 8 Downloadable Samples
Technology Badge Icon Affymetrix Mouse Genome 430 2.0 Array (mouse4302)

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We demonstrate diverse roles of interferongamma (IFN-) in the induction and regulation of immune-mediated inflammation using a transfer model of autoimmune diabetes. The diabetogenic CD4+BDC2.5 (BDC) T cell clone upon transfer into NOD.scid mice induced destruction of islets of Langerhans leading to diabetes. Administration of a neutralizing antibody to IFN- (H22) resulted in long term protection (LTP) from diabetes, with inflammation but persistence of a significant, albeit decreased numbers of -cells. BDC T cells were a mixture of cells expressing high, intermediate and low levels of the T cell receptor. Clonotype-low BDC T cells were required for LTP. Furthermore, islet infiltrating leukocytes in the LTP mice contained Foxp3+CD4 T cells. Islet inflammation in both diabetic and LTP mice was characterized by heavy infiltration of macrophages. Gene expression profiles indicated that macrophages in diabetic mice were M1-type, while LTP mice contained M2-differentiated. The LTP was abolished if mice were treated with either an antibody depleting CD4 T cells, or a neutralizing antibody to CTLA-4, in this case, only at a late stage. Neutralization of IL-10, TGF-, GITR or CD25 had no effect. Transfer of only clonotype-high expressing BDC T cells induced diabetes but in contrast, H22 antibodies did not inhibit diabetes. While clonotype high T cells induced diabetes even when IFN- was neutralized, paradoxically, there was reduced inflammation and no diabetes if host myeloid cells lacked IFN- receptor. Hence, using monoclonal CD4 T cells, IFN- can have a wide diversity of roles, depending on the setting of the immune process.
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