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

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. To date, 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 if 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 (WT) CD4+ T cells accumulate within the spleen, lung and brain of IFN-γ−/− mice and induce ECM through active IFN-γ secretion, which increases accumulation of endogenous IFN-γ−/− CD8+ T cells within the brain. Depletion of endogenous IFN-γ−/− CD8+ T cells abrogated the ability of WT 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. 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.

The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

“…Earlier studies have demonstrated that in susceptible C57BL/6 mice, T cells play a key role in the pathogenesis of ECM. Although extensive studies have indicated that CD8 + T cells and IFN-g are the important mediators of ECM, CD8 + T cells are not attributed as the primary source of IFN-g in mice undergoing the pathogenesis of ECM (38). On the other hand, how CD4 + T cells contribute toward the clinical syndrome of ECM remain poorly understood.…”

“…In addition, IFNgR2deficient mice have been shown to be resistant to ECM, and this resistance is associated with reduced levels of CD8 + T cells in the brain (37). Importantly, a recent study indicates that the major source of IFN-g that modulates ECM pathogenesis is CD4 + T cells (38). The frequency of IFN-g expressing CD4 + T cells has been found to be inherently lower in Tbx21 2/2 mice (44).…”

Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

“…Several studies have shown that anti-CD4 + Ab given around the time of PbA infection prevents ECM (26)(27)(28)(29)(30), consistent with the view that CD4 + T cell help is required for the induction of CTL responses. However, CD4 + T cells have also been implicated in CD8 + T cell recruitment to the brain (83), thus raising the possibility that their depletion merely affects this facet of disease. Only one study provides direct evidence for a contribution of CD4 + T cell help to CD8 + T cell proliferation, where CD4 + T cell depletion resulted in low proliferation of OVAspecific OT-I cells after infection with transgenic PbA parasites expressing the OVA epitope (31).…”

“…The consequences of this functional capacity for CD8 + DC, however, are likely to differ depending on the model studied, resulting in the induction of pathology or immunity. During PbA infection, for example, IFN-g-producing CD4 + T cells have been implicated in ECM by attracting CD8 + T cells to the brain (83). Thus, CD8 + DC may not only be crucial for initiation of CD8 + T cell responses leading to ECM, but also for promoting Th1 cell development that in turn facilitates IFN-g-dependent CD8 + T cell recruitment to this organ.…”

The C-Type Lectin Receptor DCIR Is Crucial for the Development of Experimental Cerebral Malaria

“…+ T cells were shown to trigger the enhanced CD8 + T cell accumulation in the brain, thus inducing ECM (12). In contrast, the immune modulatory cytokine IL-10 plays a key role in protection against severe malaria (13).…”