IFN-gamma-dependent regulatory circuits in immune inflammation highlighted in diabetes.

We demonstrate diverse roles of IFN-gamma 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 Ab to IFN-gamma (H22) resulted in long-term protection (LTP) from diabetes, with inflammation but persistence of a significant, albeit decreased, number of beta cells. BDC T cells were a mixture of cells expressing high, intermediate, and low levels of the TCR. 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 Ab-depleting CD4 T cells or a neutralizing Ab to CTLA-4, in this case, only at a late stage. Neutralization of IL-10, TGF-beta, glucocorticoid-induced TNF receptor (GITR), or CD25 had no effect. Transfer of only clonotype(high)-expressing BDC T cells induced diabetes; in contrast, H22 Abs did not inhibit diabetes. While clonotype(high) T cells induced diabetes even when IFN-gamma was neutralized, paradoxically there was reduced inflammation and no diabetes if host myeloid cells lacked IFN-gamma receptor. Hence, using monoclonal CD4 T cells, IFN-gamma can have a wide diversity of roles, depending on the setting of the immune process.

Location, allocation, relocation: isolating adult tissue stem cells in three dimensions.

The literature on isolation of adult tissue stem cells is vast and disparate. To better organize the field, we redefine 'isolation', re-expressing it as the sum of three component vectors: location, allocation and relocation. Location is the isolation of stem cells in situ by anatomical features. Allocation is physical isolation by cell sorting. Relocation is isolation of the functional properties of a stem cell to regenerate its normal progeny when relocated to a new environment. Techniques for the allocation and relocation of stem cells from certain tissues (e.g. hematopoietic) are currently better defined than their location, whereas those of other tissues (e.g. mammary glands) have had recent advances along all three vectors. Yet another group (e.g. gastric glands), have stem cells with well characterized location, emerging techniques for allocation but still rudimentary techniques for relocation.