IFN-γ-producing CD4+ T cells promote experimental cerebral malaria by modulating CD8+ T cell accumulation within the brain

Ana Villegas-Mendez, Rachel Greig, Tovah N Shaw, J Brian de Souza, Emily Gwyer Findlay, Jason S Stumhofer, Julius C R Hafalla, Daniel G Blount, Christopher A Hunter, Eleanor M Riley, Kevin N Couper

Research output: Contribution to journalArticlepeer-review

Abstract

It is well established that IFN-γ is required for the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 mice. However, the temporal and tissue-specific cellular sources of IFN-γ during P. berghei ANKA infection have not been investigated, and it is not known whether IFN-γ production by a single cell type in isolation can induce cerebral pathology. In this study, using IFN-γ reporter mice, we show that NK cells dominate the IFN-γ response during the early stages of infection in the brain, but not in the spleen, before being replaced by CD4(+) and CD8(+) T cells. Importantly, we demonstrate that IFN-γ-producing CD4(+) T cells, but not innate or CD8(+) T cells, can promote the development of ECM in normally resistant IFN-γ(-/-) mice infected with P. berghei ANKA. Adoptively transferred wild-type CD4(+) T cells accumulate within the spleen, lung, and brain of IFN-γ(-/-) mice and induce ECM through active IFN-γ secretion, which increases the accumulation of endogenous IFN-γ(-/-) CD8(+) T cells within the brain. Depletion of endogenous IFN-γ(-/-) CD8(+) T cells abrogates the ability of wild-type CD4(+) T cells to promote ECM. Finally, we show that IFN-γ production, specifically by CD4(+) T cells, is sufficient to induce expression of CXCL9 and CXCL10 within the brain, providing a mechanistic basis for the enhanced CD8(+) T cell accumulation. To our knowledge, these observations demonstrate, for the first time, the importance of and pathways by which IFN-γ-producing CD4(+) T cells promote the development of ECM during P. berghei ANKA infection.

Original languageEnglish
Pages (from-to)968-79
Number of pages12
JournalJournal of Immunology
Volume189
Issue number2
DOIs
Publication statusPublished - 15 Jul 2012

Keywords

  • Adoptive Transfer
  • Animals
  • Brain
  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Cell Movement
  • Disease Models, Animal
  • Female
  • Genetic Predisposition to Disease
  • Immunity, Innate
  • Interferon-gamma
  • Malaria, Cerebral
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Plasmodium berghei

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