The Role and Function of Regulatory T Cells in Toxoplasma gondii-Induced Adverse Pregnancy Outcomes

Gao, Xuyang; Zhong, Yue; Liu, Yifan; Ding, Runmin; Chen, Jinling

doi:10.1155/2021/8782672

Cited by 7 publications

(6 citation statements)

References 113 publications

(132 reference statements)

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“…Although expression levels of iNOS, CD8 and IFN-γ showed no significant difference between infected CXCR3KO mice and infected WT mice, FoxP3 expression was significantly decreased in infected CXCR3KO mice compared with that in infected WT mice ( p < 0.05). Although FoxP3 + Treg cells secrete some inhibitory factors including transforming growth factor-β (TGF-β) and IL-10 ( Arranz-Solís et al, 2021 ; Gao et al, 2021 ), there was no significant difference in the mRNA expression of TGF-β ( Figure 4 ) and expression of IL-10 was not detected.…”

Section: Resultsmentioning

confidence: 99%

“…FoxP3 + Treg cells primarily modulate the immune response by secreting inhibitory factors (e.g., TGF-β, IL-10, and amphiregulin) or inhibiting inflammatory cytokines produced by Th1/Th17 cells (e.g., IFN-γ, IL-17, and IL-23) to protect against their harmful effects ( Ito et al, 2019 ; Gao et al, 2021 ). In the current study, a significant reduction in FoxP3 expression levels was detected in the brain tissues of infected CXCR3KO mice at 30 dpi.…”

Section: Discussionmentioning

confidence: 99%

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Involvement of chemokine receptor CXCR3 in the defense mechanism against Neospora caninum infection in C57BL/6 mice

et al. 2023

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C-X-C motif chemokine receptor 3 (CXCR3) is an important receptor controlling the migration of leukocytes, although there is no report regarding its role in Neospora caninum infection. Herein, we investigated the relevance of CXCR3 in the resistance mechanism to N. caninum infection in mice. Wild-type (WT) C57BL/6 mice and CXCR3-knockout (CXCR3KO) mice were used in all experiments. WT mice displayed a high survival rate (100%), while 80% of CXCR3KO mice succumbed to N. caninum infection within 50 days. Compared with WT mice, CXCR3KO mice exhibited significantly lower body weights and higher clinical scores at the subacute stage of infection. Flow cytometric analysis revealed CXCR3KO mice as having significantly increased proportions and numbers of CD11c-positive cells compared with WT mice at 5 days post infection (dpi). However, levels of interleukin-6 and interferon-γ in serum and ascites were similar in all groups at 5 dpi. Furthermore, no differences in parasite load were detected in brain, spleen, lungs or liver tissue of CXCR3KO and WT mice at 5 and 21 dpi. mRNA analysis of brain tissue collected from infected mice at 30 dpi revealed no changes in expression levels of inflammatory response genes. Nevertheless, the brain tissue of infected CXCR3KO mice displayed significant necrosis and microglial activation compared with that of WT mice at 21 dpi. Interestingly, the brain tissue of CXCR3KO mice displayed significantly lower numbers of FoxP3+ cells compared with the brain tissue of WT mice at 30 dpi. Accordingly, our study suggests that the lack of active regulatory T cells in brain tissue of infected CXCR3KO mice is the main cause of these mice having severe necrosis and lower survival compared with WT mice. Thus, CXCR3+ regulatory T cells may play a crucial role in control of neosporosis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Involvement of chemokine receptor CXCR3 in the defense mechanism against Neospora caninum infection in C57BL/6 mice

et al. 2023

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“…CD4 + T cells are critical for resistance to T. gondii infection, and toxoplasmosis often leads to alterations in the number and function of CD4 + T cells ( Dupont et al., 2012 ). Studies have demonstrated that T. gondii infection inhibits Tregs proliferation, resulting in a decrease in Tregs levels ( Gao et al., 2021 ). However, T. gondii triggers a strong Th1 cell response to defend against pathogen infection ( Sana et al., 2022 ), while Th2 cells can suppress the Th1 cell response, so the Th1/Th2 balance plays a vital role during T. gondii infection ( Xu et al., 2021a ).…”

Section: Inflammation and Mood Disordersmentioning

confidence: 99%

“…Tregs, accounting for approximately 5%-10% of the total CD4 + T cells ( Gao et al., 2021 ), are crucial to maintain self-tolerance and immune homeostasis. Tregs are known as suppressor T cells, which can regulate the functions of other immune cells like DC, macrophages, CD4 + T cells, and B cells ( Hong et al., 2013 ; Mohr et al., 2018 ).…”

Section: Tregs and Mood Disordersmentioning

confidence: 99%

From the immune system to mood disorders especially induced by Toxoplasma gondii: CD4+ T cell as a bridge

Wang

Zhong

Chen

et al. 2023

Front. Cell. Infect. Microbiol.

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Toxoplasma gondii (T. gondii), a ubiquitous and obligatory intracellular protozoa, not only alters peripheral immune status, but crosses the blood-brain barrier to trigger brain parenchymal injury and central neuroinflammation to establish latent cerebral infection in humans and other vertebrates. Recent findings underscore the strong correlation between alterations in the peripheral and central immune environment and mood disorders. Th17 and Th1 cells are important pro-inflammatory cells that can drive the pathology of mood disorders by promoting neuroinflammation. As opposed to Th17 and Th1, regulatory T cells have inhibitory inflammatory and neuroprotective functions that can ameliorate mood disorders. T. gondii induces neuroinflammation, which can be mediated by CD4+ T cells (such as Tregs, Th17, Th1, and Th2). Though the pathophysiology and treatment of mood disorder have been currently studied, emerging evidence points to unique role of CD4+ T cells in mood disorder, especially those caused by T. gondii infection. In this review, we explore some recent studies that extend our understanding of the relationship between mood disorders and T. gondii.

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“…Maternal–fetal immune tolerance is crucial for a successful pregnancy, as it prevents rejection of the allogeneic fetus by the maternal immune system [ 1 ]. Early infection with T. gondii can induce adverse pregnancy outcome, which is primarily due to the disruption of maternal–fetal immune tolerance rather than the direct invasion of T. gondii [ 2 ]. Regulatory T (Treg) cells, a unique subset of CD4 + T cells, are centrally implicated in establishing and maintaining immune tolerance [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Foxp3 expression in the placenta of mice infected intraperitoneally by toxoplasma gondii tachyzoites: insights into the PPARγ/miR-7b-5p/Sp1 signaling pathway

Zhong,

Qin,

Wang

et al. 2024

Parasites Vectors

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Background Toxoplasma gondii, an obligate intracellular parasitic protozoa, infects approximately 30% of the global population. Contracting T. gondii at the primary infection of the mother can result in neonatal microcephaly, chorioretinitis, hydrocephalus, or mortality. Our previous study indicated that pregnant mice infected with T. gondii displayed a decrease in both the number and the suppressive ability of regulatory T cells, accompanied by the reduced Forkhead box P3 (Foxp3). Numerous studies have proved that microRNAs (miRNAs) are implicated in T. gondii infection, but there is meager evidence on the relationship between alterations of miRNAs and downregulation of Foxp3 induced by T. gondii. Methods Quantitative reverse transcription polymerase chain reaction was utilized to detect the transcriptions of miRNAs and Foxp3. Protein blotting and immunofluorescence were used to detect the expressions of Foxp3 and related transcription factors. The structure of mouse placenta was observed by hematoxylin and eosin (HE) staining. To examine the activity of miR-7b promoter and whether miR-7b-5p targets Sp1 to suppress Foxp3 expression, we constructed recombinant plasmids containing the full-length/truncated/mutant miR-7b promoter sequence or wildtype/mutant of Sp1 3' untranslated region (3' UTR) to detect the fluorescence activity in EL4 cells. Results In T. gondii-infected mice, miR-7b transcription was significantly elevated, while Foxp3 expression was decreased in the placenta. In vitro, miR-7b mimics downregulated Foxp3 expression, whereas its inhibitors significantly upregulated Foxp3 expression. miR-7b promoter activity was elevated upon the stimulation of T. gondii antigens, which was mitigated by co-transfection of mutant miR-7b promoter lacking peroxisome proliferator-activated receptor γ (PPARγ) target sites. Additionally, miR-7b mimics diminished Sp1 expression, while miR-7b inhibitors elevated its expression. miR-7b mimics deceased the fluorescence activity of Sp1 3' untranslated region (3' UTR), but it failed to impact the fluorescence activity upon the co-transfection of mutant Sp1 3' UTR lacking miR-7b target site. Conclusions T. gondii infection and antigens promote miR-7b transcription but inhibit Foxp3 protein and gene levels. T. gondii antigens promote miR-7b promoter activity by a PPARγ-dependent mechanism. miR-7b directly binds to Sp1 3' UTR to repress Sp1 expression. Understanding the regulatory functions by which T. gondii-induced miR-7b suppresses Foxp3 expression can provide new perspectives for the possible therapeutic avenue of T. gondii-induced adverse pregnancy outcomes. Graphical Abstract

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The Role and Function of Regulatory T Cells in Toxoplasma gondii-Induced Adverse Pregnancy Outcomes

Cited by 7 publications

References 113 publications

Involvement of chemokine receptor CXCR3 in the defense mechanism against Neospora caninum infection in C57BL/6 mice

Involvement of chemokine receptor CXCR3 in the defense mechanism against Neospora caninum infection in C57BL/6 mice

From the immune system to mood disorders especially induced by Toxoplasma gondii: CD4+ T cell as a bridge

Inhibition of Foxp3 expression in the placenta of mice infected intraperitoneally by toxoplasma gondii tachyzoites: insights into the PPARγ/miR-7b-5p/Sp1 signaling pathway

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