Studies in experimental cerebral malaria (ECM) in mice have identified T cells and TNF family members as critical mediators of pathology. In this study we report a role for LIGHT-lymphotoxin β Receptor (LTβR) signaling in the development of ECM and control of parasite growth. Specific blockade of LIGHT-LTβR, but not LIGHT-herpesvirus entry mediator interactions, abrogated the accumulation of parasites and the recruitment of pathogenic CD8+ T cells and monocytes to the brain during infection without affecting early activation of CD4+ T cells, CD8+ T cells, or NK cells. Importantly, blockade of LIGHT-LTβR signaling caused the expansion of splenic monocytes and an overall enhanced capacity to remove and process Ag during infection, as well as reduced systemic cytokine levels when control mice displayed severe ECM symptoms. In summary, we have discovered a novel pathogenic role for LIGHT and LTβR in ECM, identifying this TNF family receptor-ligand interaction as an important immune regulator during experimental malaria.

Experimental cerebral malaria (ECM),2 caused by infection of mice with Plasmodium berghei ANKA (PbA), is characterized by T cell-mediated neuropathology (1). Early immune events in the spleen during PbA infection are critical for ECM development (1, 2). Previous studies suggest that circulating and locally produced proinflammatory cytokines act on brain microvasculature to up-regulate expression of the adhesion molecules and chemokines involved in the recruitment of activated leukocytes (3). CD8+ T cells have been associated with the breakdown of the blood-brain barrier through a perforin-dependent mechanism (4).

LIGHT (TNFSF14), a member of the TNF superfamily, binds to lymphotoxin β receptor (LTβR; along with LTα1β2), herpes virus entry mediator (HVEM), and the soluble decoy receptor DcR3 with roles in innate and adaptive immunity (5). LIGHT is expressed on immature dendritic cells (DCs), activated T cells, monocytes, macrophages, and granulocytes. Signaling through HVEM is thought to provide both proinflammatory and inhibitory costimulatory signals for T cells through LIGHT and the B and T lymphocyte inhibitor BTLA, respectively (6), whereas LIGHT-LTβR interactions modulate inflammation through stromal cells but can also induce apoptosis in some malignant cells (7).

We and others have previously reported key roles for TNF family members, including TNF, LTα, and TNFRII, in the pathogenesis of ECM (8, 9, 10). In this study we show that the blockade of LIGHT-LTβR signaling protects mice from ECM.

PbA was used after one in vivo passage in mice. A transgenic PbA line expressing luciferase (PbAluc) was used for in vivo imaging studies (11, 12). Female mice (6 wk old) were from the Animal Resources Centre (Canning Vale, Australia) and housed in conventional facilities. B6.LIGHT−/− mice (13) were bred and maintained at the Queensland Institute of Medical Research (Herston, Australia) under specific pathogen-free conditions. All animal procedures were approved by the Queensland Institute of Medical Research Animal Ethics Committee.

PbA infections were established, blood parasitemia was monitored, and clinical scores were determined as previously described (2, 12). Spleen and brain mononuclear cells were isolated, flow cytometry was performed, and PbA-specific CD4+ T cell responses were measured using standard procedures (2). The Ag-processing capacity of APC was evaluated by flow cytometry using DQ-OVA (Molecular Probes) as described by others (14). Intracellular IFN-γ expression was determined by flow cytometry, LIGHT mRNA accumulation in spleen and brain tissue was measured by real-time RT-PCR using commercial reagents (Applied Biosystems), cytokine levels were determined by cytometric bead array (BD Biosciences), and bioluminescent imaging was used to determine parasite burdens, as previously described (12).

Mice were administered 100 μg of anti-LTβR mAb (LLTB2), anti-HVEM mAb (LH1) (15), control hamster IgG, or control rat IgG (Sigma-Aldrich) i.v. on the day of infection and then on day 4 postinfection (p.i.). Cell identification by flow cytometry was performed as previously reported (12).

The Kaplan-Meier log-rank test was used to identify differences in survival between treatment groups. Differences in parasitemia were analyzed using two-way ANOVA, followed by a Bonferroni posttest. Differences in cell recruitment, serum cytokine levels, mRNA accumulation, and proliferation were identified using either Student’s t test or a Mann-Whitney U test. p ≤ 0.05 was considered significant.

The role of LIGHT in ECM pathogenesis has not been determined. We first measured LIGHT mRNA accumulation during PbA infection in the spleen and brain, tissue sites where pathogenic T cell responses are generated and elicited, respectively. LIGHT mRNA accumulation was observed in the spleens of naive mice and, despite a small increase in the first 24 h after infection, declined significantly at days 3 (p < 0.05) and 6 (p < 0.01) p.i. (Fig. 1,A). In contrast, LIGHT mRNA accumulation was relatively low in the brains of naive animals (2000-fold less than in the spleen) but increased significantly (p < 0.001) in mice at day 6 p.i. when ECM symptoms were apparent (Fig. 1,A). Thus, LIGHT mRNA was present in the spleen when anti-parasitic T cell responses were first generated and increased in the brain when ECM pathology was manifest. To further elucidate the role of LIGHT in PbA infection, LIGHT-deficient C57BL/6 mice were infected with PbA and monitored for ECM symptoms. B6.LIGHT−/− mice developed ECM at the same time as control C57BL/6 mice (Fig. 1,B) but had significantly lower parasitemia on days 6 and 7 p.i. relative to controls (Fig. 1 B).

FIGURE 1.

Disruption of LIGHT-LTβR signaling protects mice from ECM. A, LIGHT mRNA accumulation was measured in spleen (left) and brain tissue (right) at indicated times after PbA infection. B, Survival (left) and blood parasitemia were monitored, as indicated, in PbA-infected C57BL/6 and B6.LIGHT−/− mice. C and D, PbA-infected mice were treated with anti-HVEM mAb (open squares) or control hamster IgG (closed squares) (C) or anti-LTβR mAb (open squares) or control rat IgG (closed squares) (D) and survival (left) and blood parasitemia (right) were monitored, as indicated. ∗, p ≤ 0.05; ∗∗, p ≤ 0.01; ∗∗∗, p ≤ 0.001.

FIGURE 1.

Disruption of LIGHT-LTβR signaling protects mice from ECM. A, LIGHT mRNA accumulation was measured in spleen (left) and brain tissue (right) at indicated times after PbA infection. B, Survival (left) and blood parasitemia were monitored, as indicated, in PbA-infected C57BL/6 and B6.LIGHT−/− mice. C and D, PbA-infected mice were treated with anti-HVEM mAb (open squares) or control hamster IgG (closed squares) (C) or anti-LTβR mAb (open squares) or control rat IgG (closed squares) (D) and survival (left) and blood parasitemia (right) were monitored, as indicated. ∗, p ≤ 0.05; ∗∗, p ≤ 0.01; ∗∗∗, p ≤ 0.001.

Close modal

Given the many different biological effects mediated by LIGHT interacting with its two cell-associated receptors (5), it is conceivable that the complete absence of LIGHT may mask important coregulatory functions for LIGHT in ECM. Therefore, we next investigated the role of each LIGHT signaling pathway in isolation using antagonistic Abs that specifically block the interaction between LIGHT and LTβR or LIGHT and HVEM, respectively, but do not disrupt other ligands binding to these receptors (15). Blocking LIGHT-HVEM interactions did not prevent or delay ECM in PbA-infected C57BL/6 mice (Fig. 1,C) or alter blood parasitemia (Fig. 1 C), compared with control-treated mice. These data indicate that LIGHT-HVEM interactions do not contribute to ECM pathogenesis following PbA infection.

Strikingly, blockade of LIGHT-LTβR interactions prevented ECM in PbA-infected mice (Fig. 1,D) and was associated with reduced blood parasitemia up until day 10 p.i. (Fig. 1,D), relative to control mice. Despite this dramatic effect on ECM development, mice treated with anti-LTβR mAb did eventually die with hyperparasitemia and severe anemia around 3 wk p.i. (Fig. 1 D). Protection from ECM required anti-LTβR mAb treatment before infection and on day 4 p.i. and was not achieved by giving a single dose of Ab at the time of infection (data not shown). Together, these results identify a critical negative regulatory role for the LIGHT-LTβR signaling pathway during PbA infection that contributes to ECM development and suppresses control of parasite growth.

The accumulation of parasites in cerebral vasculature and the recruitment of leukocytes to the brain are important steps in ECM pathogenesis (1, 16). To assess these disease parameters, C57BL/6 mice were infected with PbAluc and administered anti-LTβR mAb or control rat IgG. Whole body and brain parasite burdens were then determined by measuring bioluminescence from PbAluc when control animals developed severe ECM symptoms (Fig. 2, A and C). Importantly, whole body parasite burden in anti-LTβR-treated mice was significantly reduced (p < 0.05) compared with control mice (Fig. 2, A and C), similar to patterns of blood parasitemia at the same time (Fig. 2,D). Mice were then sacrificed and perfused to remove nonadherent cells from the brain vasculature. Brains were removed and parasite accumulation was again visualized by measuring bioluminescence. Similar to whole body parasite burdens, brains from mice treated with anti-LTβR mAb had significantly lower parasite accumulation compared with control mice (Fig. 2, B and E). Thus, both total parasite burden, a key factor in the development of severe malaria in humans (17), as well as parasite burden in the brain, a key site of tissue pathology in ECM, were markedly reduced by blocking LIGHT-LTβR interactions. Histological examination revealed pinocytic nuclei in the neurons within the cortex of the majority of control brain tissue at ECM, but not in brain tissue from anti-LTβR mAb-treated mice at this time point (data not shown), suggesting that these neurons may be undergoing apoptosis or necrosis. Otherwise, no gross morphological differences were identified between control-treated and anti-LTβR mAb-treated brain tissue by histology.

FIGURE 2.

LTβR blockade reduces parasite burden and leukocyte recruitment to the brain in PbA-infected mice. Mice were infected with PbAluc and treated with either control rat IgG (hatched bars) or anti-LTβR (filled bars) mAb, as indicated. Both treatment groups were anesthetized and injected with luciferin, and the parasite burden in whole body (A) and perfused brain tissue (B) was visualized with an in vivo imaging system when control mice developed severe ECM symptoms. Bioluminescence in whole body (C) and brain tissue (E) was measured (n = 5 mice per group). Blood parasitemia was also measured by blood smear in both groups at this time point (D). Leukocytes recruited to brain tissue of naive (open), control rat IgG-treated, and anti-LTβR-treated mice were compared by FACS, and the total cell (F), CD8+ T cell (CD8+TCR+) (G), and monocyte/macrophage (CD11b+Ly6C+) (H) counts are shown. FACS plots are individual representatives taken from one experiment of two performed. Percentages are the mean for the group. ∗, p ≤ 0.05; ∗∗, p ≤ 0.01; ∗∗∗, p ≤ 0.001.

FIGURE 2.

LTβR blockade reduces parasite burden and leukocyte recruitment to the brain in PbA-infected mice. Mice were infected with PbAluc and treated with either control rat IgG (hatched bars) or anti-LTβR (filled bars) mAb, as indicated. Both treatment groups were anesthetized and injected with luciferin, and the parasite burden in whole body (A) and perfused brain tissue (B) was visualized with an in vivo imaging system when control mice developed severe ECM symptoms. Bioluminescence in whole body (C) and brain tissue (E) was measured (n = 5 mice per group). Blood parasitemia was also measured by blood smear in both groups at this time point (D). Leukocytes recruited to brain tissue of naive (open), control rat IgG-treated, and anti-LTβR-treated mice were compared by FACS, and the total cell (F), CD8+ T cell (CD8+TCR+) (G), and monocyte/macrophage (CD11b+Ly6C+) (H) counts are shown. FACS plots are individual representatives taken from one experiment of two performed. Percentages are the mean for the group. ∗, p ≤ 0.05; ∗∗, p ≤ 0.01; ∗∗∗, p ≤ 0.001.

Close modal

The composition of leukocytes in brains was next determined. As expected (4, 12), PbA-infected control mice had significant recruitment of leukocytes to the brain with ECM (Fig. 2,F). In contrast, mice treated with the anti-LTβR mAb had limited recruitment of leukocytes and, importantly, the accumulation of both CD8+ T cells and monocytes in brain tissue was significantly reduced in these mice, compared with controls (Fig. 2, F–H). Therefore, blockade of the LIGHT-LTβR signaling pathway during PbA infection prevented the recruitment of key cellular mediators of ECM pathogenesis to the brain. Interestingly, LTβR was constitutively and most highly expressed on splenic monocytes/macrophages (CD11b+, Ly6C+) in naive and PbA-infected mice, as well as on monocytes/macrophages in the brains of mice with ECM, whereas cerebral CD4+ T cells, but not CD8+ T cells or NK cells, in mice with ECM also expressed LTβR (data not shown).

CD8+ T cells and NK cells play important roles in ECM pathogenesis (4, 18). However, activation of splenic NK and CD8+ T cells 3 days after PbA infection, as indicated by IFN-γ production, was not affected by anti-LTβR treatment (data not shown). We also examined the ability of LIGHT-LTβR blockade to modulate parasite-specific CD4+ T cell activation. Splenic CD4+ T cells were isolated from PbA-infected mice at day 3 p.i., when Ag-specific CD4+ T cells can first be detected (2). CD4+ T cells from both control rat IgG- and anti-LTβR mAb-treated mice responded specifically to parasitized RBCs (pRBCs) and not normal RBCs with similar levels of proliferation (Fig. 3,A), as well as IFN-γ and TNF production (data not shown). Furthermore, analysis of splenic conventional DC (cDC) by flow cytometry also revealed decreased expression of MHCII and CD80, and increased expression of costimulatory molecules (CD86, CD40) following PbA infection, regardless of whether LIGHT-LΤβR signaling was blocked (Fig. 3 B). Together, these data suggest that the protection from ECM and reduced parasite burdens in mice receiving LIGHT-LTβR blockade was not caused by changes in cDC, NK cell, CD4+ T cell, or CD8+ T cell activation early in PbA infection. The data also clarify that protection from ECM by blocking LIGHT-LTβR interactions is not caused by greater amounts of LIGHT being available to signal via HVEM and act as a costimulatory signal for T cell activation, as suggested in other experimental models (19).

FIGURE 3.

Cell activation and cytokine levels during PbA infection in the absence of LIGHT-LTβR interactions. A, Proliferation of splenic CD4+ T cells from naive (open bars) or PbA-infected C57BL/6 mice (day 3 p.i.) that had received anti-LTβR mAb (filled bars) or control rat IgG (hatched bars) in the presence of naive irradiated splenic APCs pulsed with normal RBCs (nRBC) or pRBCs, as indicated. B, Costimulatory molecule expression, as indicated, on splenic cDCs (CD11chigh) isolated from naive, control rat IgG-treated, and anti-LTβR mAb-treated PbA-infected mice on day 3 p.i. C–F, Serum IFN-γ (C), TNF (D), IL-6 (E), and IL-10 (F) levels in control rat IgG- and anti-LTβR mAb-treated groups during PbA infection. ∗, p ≤ 0.05; ∗∗, p ≤ 0.01.

FIGURE 3.

Cell activation and cytokine levels during PbA infection in the absence of LIGHT-LTβR interactions. A, Proliferation of splenic CD4+ T cells from naive (open bars) or PbA-infected C57BL/6 mice (day 3 p.i.) that had received anti-LTβR mAb (filled bars) or control rat IgG (hatched bars) in the presence of naive irradiated splenic APCs pulsed with normal RBCs (nRBC) or pRBCs, as indicated. B, Costimulatory molecule expression, as indicated, on splenic cDCs (CD11chigh) isolated from naive, control rat IgG-treated, and anti-LTβR mAb-treated PbA-infected mice on day 3 p.i. C–F, Serum IFN-γ (C), TNF (D), IL-6 (E), and IL-10 (F) levels in control rat IgG- and anti-LTβR mAb-treated groups during PbA infection. ∗, p ≤ 0.05; ∗∗, p ≤ 0.01.

Close modal

PbA infection not only impacts on brain function, but can also affect other visceral tissues (11). Therefore, we next measured serum cytokine levels as a general marker of inflammation in PbA-infected mice after LIGHT-LTβR blockade. Consistent with findings above in splenic lymphocyte populations, serum IFN-γ levels were not significantly different between anti-LTβR mAb- and control-treated mice on day 3 or 5 p.i. (Fig. 3, C–F). However, TNF, IL-6, IFN-γ, and IL-10 levels dropped dramatically on day 7 p.i. in anti-LTβR mAb-treated, but not in control mice, when the latter group had severe ECM symptoms (Fig. 3, C–F). This result suggests that continued LIGHT-LTβR signaling contributes to inflammation in PbA-infected mice around the time of ECM development. However, we do not yet know whether reduced systemic cytokine production in mice receiving anti-LTβR mAb contributes to their protection from ECM or whether it is a consequence of a failure of some other pathogenic mechanism developing in these mice. Analysis of annexin V staining and intracellular Bcl-2 levels at day 5 p.i. indicated that anti-LTβR treatment did not cause increased apoptosis in T cells, monocytes/macrophages, or DCs (data not shown), suggesting that increased cellular apoptosis did not account for the reduced systemic cytokine production. In fact, intracellular Bcl-2 levels were significantly higher in CD11b+, Ly6C+ monocytes/macrophages from anti-LTβR mAb-treated mice at day 5 p.i. compared with controls (data not shown).

The enhanced control of parasite growth following anti-LTβR mAb treatment could not be explained by increased lymphocyte activation. Therefore, we next investigated whether changes to innate immune mechanisms might contribute to the increased antiparasitic responses generated by LIGHT-LTβR blockade early in PbA infection. A small but not statistically significant increase in spleen cell number was observed in PbA-infected mice treated with anti-LTβR mAb, relative to control mice (Fig. 4,A). However, the monocyte/macrophage compartment, and no other cell population studied, was selectively expanded in the spleens of anti-LTβR mAb-treated mice compared with controls (Fig. 4,B). Surprisingly, an expansion in the monocyte/macrophage compartment (CD11b+, Ly6C+) was also observed in naive mice 24 h after receiving anti-LTβR mAb treatment, indicating an important role for LIGHT-LTβR in monocyte homeostasis in the spleen (data not shown). To assess the Ag uptake and processing potential of these cells and other APCs, splenocytes from anti-LTβR mAb-treated and control rat IgG-treated mice on day 3 p.i. were incubated with DQ-OVA. Ag uptake and processing by cDC (CD11chigh; Fig. 4,C) and monocytes/macrophages (CD11b+CD11c; Fig. 4,D) increased in PbA-infected mice regardless of treatment. Importantly, there was no difference in the ability of these cell subsets to take up and process Ag in the absence of LIGHT-LTβR signaling (Fig. 4, C and D). Furthermore, when uptake of GFP-transgenic PbA was measured by FACS on day 3 p.i. there was no decrease in parasite uptake by monocytes/macrophages in mice treated with anti-LTβR, relative to controls (data not shown). Together, these data show that anti-LTβR mAb treatment during PbA infection results in an expansion of splenic monocytes/macrophages and, because these cells have no reduction in Ag uptake or processing function relative to controls, LIGHT-LTβR blockade results in an overall greater capacity of the spleen to remove blood-borne Ag during PbA infection. It is unclear at present whether the enhanced numbers of myeloid cells resulted from increased mobilization of precursor cells in the bone marrow or from expansion of precursor cells in the spleen.

FIGURE 4.

Disruption of LIGHT-LTβR signaling results in the expansion of splenic monocyte/macrophages. Total splenocyte (A) and splenic monocyte/macrophage numbers (CD11b+) (B) were calculated in naive (open bars), control rat IgG-treated (hatched bars), and anti-LTβR (filled bars) mAb-treated mice on day 3 p.i. Processing of DQ-OVA by splenic cDCs (CD11chigh) (C) and macrophage/monocytes (CD11b+CD11c) (D) from naive (histogram: dotted gray line) and PbA-infected mice that received anti-LTβR mAb (histogram: dotted black line) or control rat IgG (histogram: black line), as indicated. Histograms are individual representatives taken from one experiment of two performed. The average geometric mean fluorescence intensity (MFI) (n = 5 per group) is also shown. ∗, p ≤ 0.05.

FIGURE 4.

Disruption of LIGHT-LTβR signaling results in the expansion of splenic monocyte/macrophages. Total splenocyte (A) and splenic monocyte/macrophage numbers (CD11b+) (B) were calculated in naive (open bars), control rat IgG-treated (hatched bars), and anti-LTβR (filled bars) mAb-treated mice on day 3 p.i. Processing of DQ-OVA by splenic cDCs (CD11chigh) (C) and macrophage/monocytes (CD11b+CD11c) (D) from naive (histogram: dotted gray line) and PbA-infected mice that received anti-LTβR mAb (histogram: dotted black line) or control rat IgG (histogram: black line), as indicated. Histograms are individual representatives taken from one experiment of two performed. The average geometric mean fluorescence intensity (MFI) (n = 5 per group) is also shown. ∗, p ≤ 0.05.

Close modal

In summary, we have discovered that selective blockade of LIGHT-LTβR signaling protects mice from ECM caused by PbA, thus identifying a novel and important contribution of LIGHT to malaria pathogenesis. There are at least two ways that blocking LIGHT-LTβR interactions might protect mice from ECM. First, early in PbA infection the anti-LTβR mAb treatment resulted in increased splenic monocyte/macrophage numbers, and given that there was no reduction in their ability to take up and process Ag, this may result in an enhanced ability to remove pRBCs as blood passes through the spleen, thereby lowering parasite burden and reduced pathology caused by pRBCs accumulating in tissue. LIGHT-regulated control of macrophage/monocyte expansion has not been previously reported but is conceivable because members of the monocyte lineage express LTβR (7). Second, later in infection the blockade of LIGHT-LTβR signaling caused a marked decrease in systemic cytokine levels, and because circulating and locally produced proinflammatory cytokines can act on the brain microvasculature to increase expression of adhesion molecules and chemokine receptors, leading to recruitment of activated leukocytes (8, 9, 18), this decrease in systemic cytokines may contribute to the dramatic reduction in CD8+ T cell and monocyte numbers in the brains of mice treated with anti-LTβR mAb. Studies in experimental hepatitis models have identified a pathogenic role for LIGHT through its interactions with LTβR (15), thus supporting a critical role for LIGHT-LTβR interactions in sustained inflammation. The above possibilities are not mutually exclusive, and each may contribute to the protection from ECM observed in our studies. Notably, mice deficient in HVEM have been shown to develop ECM (20). This result is consistent with our finding that specific blockade of LIGHT-HVEM interactions failed to protect mice from ECM (Fig. 1 C). Recently, mice deficient in LTβR were also found to be protected from ECM (21), further supporting an important role for LTβR in ECM pathogenesis. This latter study also reported that LTβ-deficient mice were partially resistant to ECM, suggesting a possible role for LTα1β2-LTβR interactions in ECM pathogenesis. In conclusion, our data identify LIGHT-LTβR interaction as an important immune regulatory pathway during experimental malaria.

We thank Carl Ware, Paula Norris (La Jolla Institute for Allergy and Immunology, La Jolla, CA) and Linda Richards (University of Queensland, Brisbane, Australia) for helpful advice.

The authors have no financial conflict of interest.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

2

Abbreviations used in this paper: ECM, experimental cerebral malaria; cDC, conventional dendritic cell; DC, dendritic cell; HVEM, herpesvirus entry mediator; LTβR, lymphotoxin β receptor; PbA, Plasmodium berghei ANKA; PbAluc, PbA expressing luciferase; p.i., postinfection; pRBC, parasitized RBC.

1
Hunt, N. H., G. E. Grau.
2003
. Cytokines: accelerators and brakes in the pathogenesis of cerebral malaria.
Trends Immunol.
24
:
491
-499.
2
deWalick, S., F. H. Amante, K. A. McSweeney, L. M. Randall, A. C. Stanley, A. Haque, R. D. Kuns, K. P. MacDonald, G. R. Hill, C. R. Engwerda.
2007
. Cutting edge: conventional dendritic cells are the critical APC required for the induction of experimental cerebral malaria.
J. Immunol.
178
:
6033
-6037.
3
Good, M. F., H. Xu, M. Wykes, C. R. Engwerda.
2005
. Development and regulation of cell-mediated immune responses to the blood stages of malaria: implications for vaccine research.
Annu. Rev. Immunol.
23
:
69
-99.
4
Nitcheu, J., O. Bonduelle, C. Combadiere, M. Tefit, D. Seilhean, D. Mazier, B. Combadiere.
2003
. Perforin-dependent brain-infiltrating cytotoxic CD8+ T lymphocytes mediate experimental cerebral malaria pathogenesis.
J. Immunol.
170
:
2221
-2228.
5
Ware, C. F..
2005
. Network communications: lymphotoxins, LIGHT, and TNF.
Annu. Rev. Immunol.
23
:
787
-819.
6
Murphy, K. M., C. A. Nelson, J. R. Sedy.
2006
. Balancing co-stimulation and inhibition with BTLA and HVEM.
Nat. Rev. Immunol.
6
:
671
-681.
7
Xu, Y., K. Tamada, L. Chen.
2007
. LIGHT-related molecular network in the regulation of innate and adaptive immunity.
Immunol. Res.
37
:
17
-32.
8
Engwerda, C. R., T. L. Mynott, S. Sawhney, J. B. De Souza, Q. D. Bickle, P. M. Kaye.
2002
. Locally up-regulated lymphotoxin α, not systemic tumor necrosis factor α, is the principle mediator of murine cerebral malaria.
J. Exp. Med.
195
:
1371
-1377.
9
Grau, G. E., L. F. Fajardo, P. F. Piguet, B. Allet, P. H. Lambert, P. Vassalli.
1987
. Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria.
Science
237
:
1210
-1212.
10
Lucas, R., J. N. Lou, P. Juillard, M. Moore, H. Bluethmann, G. E. Grau.
1997
. Respective role of TNF receptors in the development of experimental cerebral malaria.
J. Neuroimmunol.
72
:
143
-148.
11
Franke-Fayard, B., C. J. Janse, M. Cunha-Rodrigues, J. Ramesar, P. Buscher, I. Que, C. Lowik, P. J. Voshol, M. A. den Boer, S. G. van Duinen, et al
2005
. Murine malaria parasite sequestration: CD36 is the major receptor, but cerebral pathology is unlinked to sequestration.
Proc. Natl. Acad. Sci. USA
102
:
11468
-11473.
12
Amante, F. H., A. C. Stanley, L. M. Randall, Y. Zhou, A. Haque, K. McSweeney, A. P. Waters, C. J. Janse, M. F. Good, G. R. Hill, C. R. Engwerda.
2007
. A role for natural regulatory T cells in the pathogenesis of experimental cerebral malaria.
Am. J. Pathol.
171
:
548
-559.
13
Scheu, S., J. Alferink, T. Potzel, W. Barchet, U. Kalinke, K. Pfeffer.
2002
. Targeted disruption of LIGHT causes defects in costimulatory T cell activation and reveals cooperation with lymphotoxin β in mesenteric lymph node genesis.
J. Exp. Med.
195
:
1613
-1624.
14
Wahid, R., M. J. Cannon, M. Chow.
2005
. Dendritic cells and macrophages are productively infected by poliovirus.
J. Virol.
79
:
401
-409.
15
Anand, S., P. Wang, K. Yoshimura, I. H. Choi, A. Hilliard, Y. H. Chen, C. R. Wang, R. Schulick, A. S. Flies, D. B. Flies, et al
2006
. Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis.
J. Clin. Invest.
116
:
1045
-1051.
16
Engwerda, C., E. Belnoue, A. C. Gruner, L. Renia.
2005
. Experimental models of cerebral malaria.
Curr. Top Microbiol. Immunol.
297
:
103
-143.
17
Dondorp, A. M., V. Desakorn, W. Pongtavornpinyo, D. Sahassananda, K. Silamut, K. Chotivanich, P. N. Newton, P. Pitisuttithum, A. M. Smithyman, N. J. White, N. P. Day.
2005
. Estimation of the total parasite biomass in acute falciparum malaria from plasma PfHRP2.
PLoS Med.
2
:
e204
18
Hansen, D. S., N. J. Bernard, C. Q. Nie, L. Schofield.
2007
. NK cells stimulate recruitment of CXCR3+ T cells to the brain during Plasmodium berghei-mediated cerebral malaria.
J. Immunol.
178
:
5779
-5788.
19
Wang, J., J. C. Lo, A. Foster, P. Yu, H. M. Chen, Y. Wang, K. Tamada, L. Chen, Y. X. Fu.
2001
. The regulation of T cell homeostasis and autoimmunity by T cell-derived LIGHT.
J. Clin. Invest.
108
:
1771
-1780.
20
Lepenies, B., K. Pfeffer, M. A. Hurchla, T. L. Murphy, K. M. Murphy, J. Oetzel, B. Fleischer, T. Jacobs.
2007
. Ligation of B and T lymphocyte attenuator prevents the genesis of experimental cerebral malaria.
J. Immunol.
179
:
4093
-4100.
21
Togbe, D., P. Loureiro de Sousa, M. Fauconnier, V. Boissay, L. Fick, S. Scheu, K. Pfeffer, R. Menard, G. E. Grau, B. T. Doan, et al
2008
. Both functional LTβ receptor and TNF receptor 2 are required for the development of experimental cerebral malaria.
PLoS ONE
3
:
e2608