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Immunomodulatory effects of interferon-gamma on autoreactive nephritogenic T-cell clones
1University of Pennsylvania School of Medicine, Department of Medicine, Philadelphia, USA. meyersc@mail.med.upenn.edu
Background:
We examined the immunomodulatory effects of interferon-gamma (IFN-gamma) on renal-derived CD4+ alpha/beta + T cells, called mouse renal (MR) cells, isolated from animals with murine chronic graft-versus-host disease, a model of autoimmune glomerulonephritis. MR T cells express a Th2 cytokine profile, although IFN-gamma expression is also detected in a subset of clones that adoptively transfers renal disease to naive recipients. In view of disparate patterns of IFN-gamma expression, we evaluated the effects of exogenous IFN-gamma on nephritogenic (MR1.3) and nonnephritogenic (MR1.6) clonal activity.
Methods:
These studies examined IFN-gamma-mediated effects on clonal proliferation, cytokine production, nephritogenic potential, and IFN-gamma receptor expression.
Results:
IFN-gamma mediated dose-dependent inhibition of MR1.3 and MR1.6 proliferation. This cytostatic effect was not mediated by inhibiting cytokine genes, as expression of interleukin (IL)-4, IL-10, IL-13, and IFN-gamma after IFN-gamma treatment was not markedly altered in either clone, although baseline IL-13 expression was enhanced in MR1.6. IFN-gamma markedly altered the functional phenotype of MR1.6, as pretreated recipients developed severe mononuclear cell infiltrates and tubular damage following adoptive transfer of MR1.6. Neutralizing anti-IFN-gamma antibodies did not inhibit MR1.3 nephritogenicity, but did block MR1.6-induced disease in IFN-gamma-treated mice. Although both clones constitutively expressed the IFN-gamma receptor beta chain, IFN-gamma exposure decreased its expression in MR1.3 cells, but did not markedly change its expression in MR1.6 cells.
Conclusion:
These studies describe an unusual permissive role for IFN-gamma in modulating nephritogenic Th2 activity in vivo, which facilitates the initiation of cell-mediated autoimmune renal injury. Apparent differential effects of IFN-gamma on distinct T-cell clones may be mediated in part by alterations in cytokine receptor expression.