Imbalance of uterine innate lymphoid cells is involved in the abnormal pregnancy induced by Toxoplasma gondii infection
Introduction
Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan parasite that can infect humans and other warm-blooded animals (Deng et al., 2018; Olariu et al., 2011). T. gondii infection during pregnancy could cause adverse pregnancy outcomes such as embryonic death, resorption, fetal death, abortion, and stillbirth (Fallahi et al., 2018; Kaye, 2011). However, the mechanism of abortion and fetal death remains unknown.
The immune microenvironment at the maternal-fetal interface is closely associated with the maintenance of successful pregnancy (Miller et al., 2018; Tong and Abrahams, 2020). Within the maternal-fetal immune system, decidual NK cells were the largest population of decidual leukocytes during the first trimester (Sojka et al., 2019). NK cells are essential for controlling immune tolerance, trophoblast invasion, vascular remodeling, and fetal-placental growth (Hanna et al., 2006, Sojka et al., 2014). Trained decidual NK cells expressing high levels of IFN-γ and VEGFα, remember the first pregnancy and better assist future gestation (Gamliel et al., 2018).
Besides NK cells, other innate lymphoid cells (ILCs) have also been identified in both human and mouse uterus (Vazquez et al., 2019; Doisne et al., 2015; Vacca et al., 2015). ILCs can be divided into three subgroups based on transcription factors and cytokine production. Group 1 ILCs (ILC1 cells) constitutively express T-bet and are able to produce IFN-γ upon activation (Cording et al., 2016; Klose et al., 2014). Murine uterine ILC1 cells include tissue-resident NK (trNK) cells (Eomes+CD49a+), classical natural killer (cNK) cells (Eomes+CD49a−), and helper ILC1 cells (Eomes−CD49a+) (Sojka et al., 2019; Doisne et al., 2015; Montaldo et al., 2015). Group 2 ILCs (ILC2 cells) constitutively express GATA-3 and produce IL-5 and IL-13 (Krabbendam et al., 2018). Group 3 ILCs (ILC3 cells) express RORγt and produce IL-17 and IL-22 (Klose et al., 2014; Juelke and Romagnani, 2016). Our previous and other studies showed that uterine ILCs (uILCs), especially ILC2 cells increased significantly during pregnancy and played an important role in uterine vascular adaptation for successful pregnancy (Li et al., 2017; Boulenouar et al., 2016). However, the role of uILCs in T. gondii-induced pregnancy failure is not clear.
In this study, using the model of pregnancy failure caused by T. gondii infection, we found that the proportions and numbers of uILC2 and uILC3 were decreased whereas the proportion and number of uILC1 were increased in T. gondii-infected mice. It is worth noting that, IL-12, IL-18, IL-12Rβ2, and IL-18Rα were increased in T. gondii-infected mice. In vitro experiments confirmed that IL-12 and IL-18 induced the imbalance of uILCs. Overall, our data revealed the imbalance of uILCs caused by T. gondii infection, which might contribute to the adverse pregnancy induced by T. gondii infection.
Section snippets
Mice and mating
C57BL/6 mice (8–10 weeks old) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. All mice were kept under specific pathogen-free microenvironment. All animal procedures were conducted in accordance with the National Guidelines for Animal Use in Research (China). The protocols for animal experiments were approved by the ethics committee at Anhui Medical University. All mice were housed (four mice/cage) at 25℃-26℃ on a 12 h light dark cycle, with free access to water
Altered ILC composition in the uteri of T. gondii-infected pregnancy mice
As previously reported, T. gondii infection caused adverse pregnancy in pregnant mice (Fig. S1A–C). To examine the role of uILCs in T. gondii-induced adverse pregnancy, we determined uILCs at gd9.5 (mid-gestation) after T. gondii infection. We used enzymatic protocol to isolate uterine MNCs, and we confirmed that Collagenase IV digestion did not cause CD3 shedding (Fig. S2A–C). Our results showed that the percentage and number of CD45+CD3−CD19−CD11b−Ly6G/C−Thy1.2+ ILCs in the uteri were
Discussion
The immune microenvironment at the maternal-fetal interface is crucial to maintain successful pregnancy (Tong and Abrahams, 2020; Zhang and Sun, 2020). T. gondii infection is known to lead abnormal pregnancy by disrupting the immune balance at the maternal-fetal interface (Piao et al., 2018; Zhao et al., 2017). Our previous study showed that uterine ILCs play an important role in uterine vascular adaptation for successful pregnancy (Li et al., 2017). However, the role of uILCs in T. gondii
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgement
This work was supported by the National Natural Science Foundation of China(#81870410).
References (42)
- et al.
Interleukin-12 and -23 control plasticity of CD127(+) group 1 and group 3 innate lymphoid cells in the intestinal lamina propria
Immunity
(2015) Innate lymphoid cells: diversity, plasticity, and unique functions in immunity
Immunity
(2018)- et al.
An updated literature review on maternal-fetal and reproductive disorders of Toxoplasma gondii infection
J. Gynecol. Obstet. Hum. Reprod.
(2018) - et al.
Differentiation of human innate lymphoid cells (ILCs)
Curr. Opin. Immunol.
(2016) Toxoplasmosis: diagnosis, treatment, and prevention in congenitally exposed infants
J. Pediatr. Health Care
(2011)- et al.
Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages
Cell
(2014) - et al.
Molecular signature and functional analysis of uterine ILCs in mouse pregnancy
J. Reprod. Immunol.
(2017) - et al.
The immunobiology of the innate response to Toxoplasma gondii
Int. J. Parasitol.
(2009) - et al.
Immunology of the placenta
Obstet. Gynecol. Clin. N. Am.
(2020) - et al.
Identification of diverse innate lymphoid cells in human decidua
Mucosal Immunol.
(2015)
Differential regulation and function of the Fas/Fas ligand system in human trophoblast cells
Biol. Reprod.
IL-1beta, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation in the lungs
Nat. Immunol.
Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues
Nat. Immunol.
The residual innate lymphoid cells in NFIL3-deficient mice support suboptimal maternal adaptations to pregnancy
Front. Immunol.
Tolerance to the foetal allograft?
Am. J. Reprod. Immunol.
Innate lymphoid cells in defense, immunopathology and immunotherapy
Nat. Immunol.
Seroprevalence of Toxoplasma gondii in pregnant women and livestock in the mainland of China: a systematic review and hierarchical meta-analysis
Sci. Rep.
Composition, development, and function of uterine innate lymphoid cells
J. Immunol.
Trained memory of human uterine NK cells enhances their function in subsequent pregnancies
Immunity
Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells
Nat. Immunol.
Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs
Science
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