Macrophage migration inhibitory factor (MIF) exerts either a protective or a deleterious role in the immune response to different pathogens. We analyzed herein the role of MIF in the host control of toxoplasmosis using MIF ^−/− mice backcrossed to either the BALB/c or the C57BL/6 genetic backgrounds. Both, wild‐type (WT) BALB/c and MIF ^−/− BALB/c mice were susceptible to infection with highly virulent RH as well as moderately virulent ME49 strains of T. gondii .MIF ^−/− mice, however, showed greater liver damage and more brain cysts, produced less proinflammatory cytokines, and succumbed significantly faster than WT mice. Bone marrow‐derived dendritic cells (BMDCs) from MIF ^−/− mice produced less interleukin‐1β, interleukin‐12, and tumor necrosis factor‐α than WT BMDCs after stimulation with soluble Toxoplasma antigen (STAg). Similar observations were made in CD11c ⁺ low‐density cells isolated from the spleens of MIF ^−/− mice challenged with STAg. MIF ^−/− C57BL/6 mice succumbed to ME49 infection faster than their WT counterparts. C57BL/6 mice that succumbed to infection with the ME49 strain produced less MIF than resistant BALB/c mice similarly infected. Interestingly, an analysis of brains from patients with cerebral toxoplasmosis showed low levels of MIF expression. Together, these findings demonstrate that MIF plays a critical role in mediating host resistance against T. Gondii. —Flores, M., Saavedra, R., Bautista, R., Viedma, R., Tenorio, E. P., Leng, L., Sánchez, Y., Juárez, I., Satoskar, A. A., Shenoy, A. S., Terrazas, L. I., Bucala, R., Barbi J., Satoskar, A. R., Rodriguez‐Sosa, M. Macrophage migration inhibitory factor (MIF) is critical for the host resistance against Toxoplasma gondii. FASEB J. 22, 3661–3671 (2008)

To determine the role of STAT4-dependent Th1 responses in the regulation of immunity to the helminth parasiteTaenia crassiceps, we monitored infections with this parasite in resistant mice lacking the STAT4 gene. WhileT. crassiceps-infected STAT4^+/+mice rapidly resolved the infection, STAT4^−/−mice were highly susceptible to infection and displayed large parasite loads. Moreover, the inability of STAT4^−/−mice to control the infection was associated with the induction of an antigen-specific Th2-type response characterized by significantly higher levels of Th2-associated immunoglobulin G1 (IgG1) and total IgE as well as interleukin-4 (IL-4), IL-10, and IL-13 than those in STAT4^+/+mice, who produced significantly more gamma interferon. Furthermore, early after infection, macrophages from STAT4^−/−mice produced lower levels of the pro-inflammatory cytokines IL-12, tumor necrosis factor alpha, IL-1β, and nitric oxide (NO) than those from STAT4^+/+mice, suggesting a pivotal role for macrophages in mediating protection against cysticercosis. These findings demonstrate a critical role for the STAT4 signaling pathway in the development of a Th1-type immune response that is essential for mediating protection against the larval stage ofT. crassicepsinfection.

Acute Toxoplasma gondii infection comprises an immunosuppression stage, characterized by a reduction in T‐cell proliferation in vitro. Treg cells maintain the homeostasis of the immune system, but their role in T. gondii‐induced suppression has not been addressed. We show herein that immunosuppression, affecting both CD4⁺ and CD8⁺ T‐cell proliferation, concurs with a reduction in Treg‐cell number. The residual Treg cells, however, are activated and display an increased suppressive capacity. We show that selective elimination of Treg cells using Foxp3^EGFP mice leads to a full recovery of CD4⁺ and CD8⁺ T‐cell proliferation. After Treg‐cell removal, a reduced production of IL‐10 was observed, but IL‐2 levels were unchanged. The numbers of IL‐10‐producing Treg cells also increased during infection, although the in vitro neutralization of this cytokine did not modify T‐cell proliferation, suggesting that IL‐10 does not mediate the Treg‐mediated suppression. However, addition of rIL‐2 in vitro fully restored T‐cell proliferation from infected animals. Thus, we show that Treg cells mediate the T‐cell suppression observed during acute T. gondii infection through an IL‐2‐dependent mechanism. Our results provide novel insights into the regulation of the immune response against T. gondii.