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

Villegas-Mendez, A, Greig, R, Shaw, TN, de, Souza JB, Gwyer, Findlay E, Stumhofer, JS, Hafalla, JC, Blount, DG, Hunter, CA, Riley, EM and Couper, KN (2012) IFN-γ-producing CD4+ T cells promote experimental cerebral malaria by modulating CD8+ T cell accumulation within the brain. Journal of immunology (Baltimore, Md. : 1950), 189 (2), 968–979. (doi:10.4049/jimmunol.1200688).

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.

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Contributors

Author: Findlay E Gwyer

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