Removal of regulatory T cell activity reverses hyporesponsiveness and leads to filarial parasite clearance in vivo

MD Taylor, L LeGoff, A Harris, E Malone, JE Allen, RM Maizels*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Human filarial parasites cause chronic infection associated with long-term down-regulation of the host's immune response. We show here that CD4+ T cell regulation is the main determinant of parasite survival. In a laboratory model of infection, using Litomosoides sigmodontis in BALB/c mice, parasites establish for >60 days in the thoracic cavity. During infection, CD4+ T cells at this site express increasing levels of CD25, CTLA-4, and glucocorticoid-induced TNF receptor family-related gene (GITR), and by day 60, up to 70% are CTLA-4(+)GITR(high), with a lesser fraction coexpressing CD25. Upon Ag stimulation, CD4(+)CTLA-4(+)GITR(high) cells are hyporesponsive for proliferation and cytokine production. To test the hypothesis that regulatory T cell activity maintains hyporesponsiveness and prolongs infection, we treated mice with Abs to CD25 and GITR. Combined Ab treatment was able to overcome an established infection, resulting in a 73% reduction in parasite numbers (p <0.01). Parasite killing was accompanied by increased Ag-specific immune responses and markedly reduced levels of CTLA-4 expression. The action of the CD25(+)GITR+ cells was IL-10 independent as in vivo neutralization of IL-10R did not restore the ability of the immune system to kill parasites. These data suggest that regulatory T cells act, in an IL-10-independent manner, to suppress host immunity to filariasis.
Original languageEnglish
Pages (from-to)4924-4933
Number of pages10
JournalJournal of Immunology
Volume174
Issue number8
Publication statusPublished - 15 Apr 2005

Keywords

  • Animals
  • Antibodies, Monoclonal
  • Antigens, CD
  • Antigens, Differentiation
  • Antilymphocyte Serum
  • CD4-Positive T-Lymphocytes
  • Cell Proliferation
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Female
  • Filariasis
  • Filarioidea
  • Forkhead Transcription Factors
  • Gene Expression
  • Humans
  • Interleukin-10
  • Lymphocyte Activation
  • Lymphocyte Depletion
  • Mice
  • Mice, Inbred BALB C
  • Receptors, Interleukin-2
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Th1 Cells
  • Th2 Cells
  • Transforming Growth Factor beta

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