IFN-γ-Producing CD4+ T Cells Promote Experimental Cerebral Malaria by Modulating CD8+ T Cell Accumulation within the Brain

It is well established that IFN-gamma 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-gamma during P. berghei ANKA infection have not been investigated, and it is not known whether IFN-gamma production by a single cell type in isolation can induce cerebral pathology. In this study, using IFN-gamma reporter mice, we show that NK cells dominate the IFN-gamma 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-gamma-producing CD4(+) T cells, but not innate or CD8(+) T cells, can promote the development of ECM in normally resistant IFN-gamma(-/-) mice infected with P. berghei ANKA. Adoptively transferred wild-type CD4(+) T cells accumulate within the spleen, lung, and brain of IFN-gamma(-/-) mice and induce ECM through active IFN-gamma secretion, which increases the accumulation of endogenous IFN-gamma(-/-) CD8(+) T cells within the brain. Depletion of endogenous IFN-gamma(-/-) CD8(+) T cells abrogates the ability of wild-type CD4(+) T cells to promote ECM. Finally, we show that IFN-gamma 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-gamma-producing CD4(+) T cells promote the development of ECM during P. berghei ANKA infection. The Journal of Immunology, 2012, 189: 968-979.