Immunomodulatory effects of interferon-gamma on autoreactive nephritogenic T-cell clones

Kidney Int. 1999 Apr;55(4):1395-406. doi: 10.1046/j.1523-1755.1999.00394.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adjuvants, Immunologic / pharmacology*
  • Adoptive Transfer
  • Animals
  • Antibodies / metabolism
  • Antibodies / pharmacology
  • Autoimmunity / drug effects
  • Autoimmunity / immunology*
  • Binding, Competitive
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Division / drug effects
  • Clone Cells / cytology
  • Clone Cells / immunology
  • Clone Cells / metabolism
  • Cytokines / biosynthesis
  • Disease Models, Animal
  • Glomerulonephritis / immunology*
  • Interferon-gamma / metabolism
  • Interferon-gamma / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Receptors, Interferon / biosynthesis
  • Th2 Cells / immunology

Substances

  • Adjuvants, Immunologic
  • Antibodies
  • Cytokines
  • Receptors, Interferon
  • interferon gamma receptor
  • Interferon-gamma