Role of CD4⁺Foxp3⁺Regulatory T Cells in Protection Induced by a Live Attenuated, Replicating Type I Vaccine Strain of Toxoplasma gondii

Abstract

Toxoplasmosis is caused by a protozoan parasite that infects humans and other warm-blooded animals. Infections in humans are generally asymptomatic, although immunosuppressed patients may exhibit severe symptoms. Similarly, primary infection during pregnancy can lead to miscarriage and neonatal malformations. Toxoplasmosis can be transmitted to humans via ingestion of oocysts or via the consumption of meat products contaminated with tissue cysts (1). Effective vaccination of domestic livestock can therefore prevent human infection with Toxoplasma gondii. It is possible to induce strong protection by immunization with a live attenuated strain (2). Live attenuated vaccine strain models are also useful for advancing the understanding of the protective host immune response (3-8). However, the information available about the mechanism of protection involved after vaccination with a type I attenuated strain was obtained with nonreplicating, nonpersistent strains, such as strains cps-1 (3-7) and ts4 (8). A strain known as Mic1.3KO was obtained in our laboratory by deleting the MIC1 and MIC3 genes (9). This strain was derived from the highly virulent type I RH strain, and its reduced invasion capacity in vitro was correlated with decreased virulence when injected into outbred Swiss OF1 mice (9). Type I strains are characterized by the rapid dissemination of the parasite and by a high parasite burden that results in death soon after infection by a single viable parasite in mice (10). High levels of gamma interferon (IFN-␥) were produced following infection with a type I parasite, and mice succumbed to uncontrolled parasite growth and associated inflammation (11,12). The Mic1.3KO strain with the MIC1 and MIC3 gene deletions showed reduced virulence, lower levels of dissemination throughout tissues, and lower levels of IFN-␥ production than the parental RH strain after injection into mice (13).In a model of lethal toxoplasmosis induced after oral administration of infection with a type II strain causing infection in C57BL/6 mice, overproduction of IFN-␥ was also responsible for mortality and was correlated with a sharp decline in the percentage of regulatory T cells (Tregs) just before death, supporting the hypothesis of defective immunoregulation (14). Tregs are a subpopulation of CD4 ϩ T cells, and their main function is to maintain immune homeostasis and tolerance (15). They constitutively express the interleukin-2 (IL-2) receptor alpha chain (IL2R␣), a surface receptor also known as CD25, and the intracellular fork head box-p3 transcription factor (Foxp-3) marker (16). The role of Tregs after infection with type II strains has been fully described (14,(17)(18)(19)(20)(21), and Tregs have been clearly implicated in the mortality of C57BL/6 mice after oral infection in the lethal ileitis model (14). The collapse of Tregs is correlated with pathogenicity and occurs only under highly pathogenic conditions since oral infection of BALB/c mice with a type II strain did not induce a reduction in the levels of Tregs (14). Howev...

Treatment of mice with S4B6 IL-2 complex prevents lethal toxoplasmosis via IL-12- and IL-18-dependent interferon-gamma production by non-CD4 immune cells

“…7 j) and T Reg numbers in MLN and lamina propria were not increased by IL2C injections (Fig. 7 k–m) suggesting a role for IL2C pre-treatment independent of the previously reported T Reg expansion with JES6-1A12-containing IL2C 40 , 41 . Collectively, these results demonstrate a protective role of IL2C pre-treatment in acute lethal murine toxoplasmosis that is dependent on IL-12, IL-18 and IFN-γ but is independent from effects on parasite burden.…”

“…Using JES6-1A12-containing IL2C, Akbar et al 41 showed that selective expansion of T Reg cells in Type I T. gondii RH-infected animals improved control of the parasite. It was also demonstrated that T Reg expansion with JES6-1A12-containing IL2C can overcome the competition for bioavailable IL-2 by regulatory and effector T cells, leading to reduced immunopathology and morbidity during acute Type II T. gondii ME49 infection 40 .…”

T‐cell profiles elicited by Toxoplasma gondii in acutely/chronically infected humans

“…In contrast, a recent report showed an increase in the Treg response after infection with the vaccine strain. This increase was temporary and was followed by increases in Treg effector cells, which were correlated with T. gondii control . Our data show that rMAG induced a significant increase in Treg in CIP, an interesting finding due to the relevance of this subpopulation in the control of T. gondii infection.…”

Treatment of mice with IL2-complex enhances inflammasome-driven IFN-γ production and prevents lethal toxoplasmosis

“…At 9 days after infection, IL2C pre-treated mice displayed significantly reduced gross pathology of gut and liver (Fig 7G, H) in the absence of any effect on parasite burden (Fig 7I). TReg numbers in MLN and lamina propria (LP) were not increased after IL2C injections (Fig 7J, K, L) suggesting a role for IL2C pre-treatment independent of the previously reported TReg expansion with JES6-1A12-containing IL2C [40,41]. Collectively, these results demonstrate a protective role of IL2C pre-treatment in acute lethal murine toxoplasmosis.…”

“…Using JES6-1A12-containing IL2C, Akbar et al [41] showed that selective expansion of TReg cells in Type I T. gondii RH-infected animals improved control of the parasite. It was also demonstrated that TReg expansion with JES6-1A12-containing IL2C can overcome the competition for bioavailable IL-2 by regulatory and effector T cells, leading to reduced immunopathology and morbidity during acute Type II T. gondii ME49 infection [40].…”