Type I interferons suppress CD4⁺ T-cell-dependent parasite control during blood-stage Plasmodium infection

Eur J Immunol. 2011 Sep;41(9):2688-98. doi: 10.1002/eji.201141539. Epub 2011 Aug 8.

Abstract

During blood-stage Plasmodium infection, large-scale invasion of RBCs often occurs before the generation of cellular immune responses. In Plasmodium berghei ANKA (PbA)-infected C57BL/6 mice, CD4(+) T cells controlled parasite numbers poorly, instead providing early help to pathogenic CD8(+) T cells. Expression analysis revealed that the transcriptional signature of CD4(+) T cells from PbA-infected mice was dominated by type I IFN (IFN-I) and IFN-γ-signalling pathway-related genes. A role for IFN-I during blood-stage Plasmodium infection had yet to be established. Here, we observed IFN-α protein production in the spleen of PbA-infected C57BL/6 mice over the first 2 days of infection. Mice deficient in IFN-I signalling had reduced parasite burdens, and displayed none of the fatal neurological symptoms associated with PbA infection. IFN-I substantially inhibited CD4(+) T-bet(+) T-cell-derived IFN-γ production, and prevented this emerging Th1 response from controlling parasites. Experiments using BM chimeric mice revealed that IFN-I signalled predominantly via radio-sensitive, haematopoietic cells, but did not suppress CD4(+) T cells via direct signalling to this cell type. Finally, we found that IFN-I suppressed IFN-γ production, and hampered efficient control of parasitaemia in mice infected with non-lethal Plasmodium chabaudi. Thus, we have elucidated a novel regulatory pathway in primary blood-stage Plasmodium infection that suppresses CD4(+) T-cell-mediated parasite control.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / parasitology
  • CD8-Positive T-Lymphocytes / pathology
  • Cells, Cultured
  • Immune Evasion
  • Immunosuppression
  • Interferon Type I / immunology
  • Interferon Type I / metabolism*
  • Interferon-gamma / metabolism
  • Life Cycle Stages
  • Malaria / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Plasmodium berghei / immunology*
  • Plasmodium berghei / pathogenicity
  • Plasmodium chabaudi / immunology*
  • Plasmodium chabaudi / pathogenicity
  • Signal Transduction / immunology
  • T-Box Domain Proteins / metabolism
  • Th1 Cells / immunology
  • Th1 Cells / metabolism*
  • Th1 Cells / parasitology
  • Th1 Cells / pathology
  • Transplantation Chimera
  • Virulence

Substances

  • Interferon Type I
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Interferon-gamma