CTLA-4 and CD4+ CD25+ regulatory T cells inhibit protective immunity to filarial parasites in vivo

Matthew D Taylor, Anjanette Harris, Simon A Babayan, Odile Bain, Abigail Culshaw, Judith E Allen, Rick M Maizels

Research output: Contribution to journalArticlepeer-review

Abstract

The T cell coinhibitory receptor CTLA-4 has been implicated in the down-regulation of T cell function that is a quintessential feature of chronic human filarial infections. In a laboratory model of filariasis, Litomosoides sigmodontis infection of susceptible BALB/c mice, we have previously shown that susceptibility is linked both to a CD4+ CD25+ regulatory T (Treg) cell response, and to the development of hyporesponsive CD4+ T cells at the infection site, the pleural cavity. We now provide evidence that L. sigmodontis infection drives the proliferation and activation of CD4+ Foxp3+ Treg cells in vivo, demonstrated by increased uptake of BrdU and increased expression of CTLA-4, Foxp3, GITR, and CD25 compared with naive controls. The greatest increases in CTLA-4 expression were, however, seen in the CD4+ Foxp3- effector T cell population which contained 78% of all CD4+ CTLA-4+ cells in the pleural cavity. Depletion of CD25+ cells from the pleural CD4+ T cell population did not increase their Ag-specific proliferative response in vitro, suggesting that their hyporesponsive phenotype is not directly mediated by CD4+ CD25+ Treg cells. Once infection had established, killing of adult parasites could be enhanced by neutralization of CTLA-4 in vivo, but only if performed in combination with the depletion of CD25+ Treg cells. This work suggests that during filarial infection CTLA-4 coinhibition and CD4+ CD25+ Treg cells form complementary components of immune regulation that inhibit protective immunity in vivo.
Original languageEnglish
Pages (from-to)4626-34
Number of pages9
JournalJournal of Immunology
Volume179
Issue number7
Publication statusPublished - 2007

Keywords

  • Animals
  • Antibody Formation
  • Antigens, CD
  • Antigens, Differentiation
  • CD4-Positive T-Lymphocytes
  • Cell Survival
  • Cells, Cultured
  • Female
  • Filariasis
  • Filarioidea
  • Forkhead Transcription Factors
  • Interleukin-2 Receptor alpha Subunit
  • Mice
  • Mice, Inbred BALB C

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