Regulatory T Cells in Development and Prediction of Necrotizing Enterocolitis in Preterm Neonates: A Scoping Review
Abstract
:1. Introduction
2. Methods
3. Results
3.1. Study Results
3.2. The role of Different T Cell Subsets in NEC
3.2.1. Treg Number in NEC
3.2.2. The Influence of Th17 Cells on the Inflammatory State in NEC
3.2.3. Increased Levels of CCR9 + Tregs in NEC
Author | Year | Study Design | Species | Sample Size | NEC Induction | Methods | Histological NEC Score | Flow Cytometry | T Cell Markers | Most Relevant Findings |
---|---|---|---|---|---|---|---|---|---|---|
Huenecke [14] | 2016 | Case control | Human | 50 total, 40 cases, preterm; 10 controls, term | No | Infants grouped based on GA. Immune cell subsets were analyzed on PB samples. | No | Yes: on blood | Treg: CD4+ + CD25+ + CD127dim; naive T cells: CD3+ + CD4+ or CD8+ + CD45RA+ + CD62L+; central memory T cells: CD3+ + CD4+ or CD8+ + CD45RO+ + CD62L+; effector memory T cells: CD3+ + CD4+ or CD8+ + CD45RO+ + CD62L−; effector memory RA T cells: CD3+ + CD4+ or CD8+ + CD45RA+ + CD62L− | B cell numbers were decreased in preterm infants compared to term infants at time of birth. Tregs frequency was highest in preterm infants at GA of 26 weeks, but declined during first weeks of life. |
Weitkamp [15] | 2009 | Case study | Human | 59 total, all intestinal surgical cases | No | Remnant human tissue samples of intestinal surgical cases of NEC, perinatal spontaneous intestinal perforation, and congenital intestinal obstruction. Immunohistochemistry was performed. | No | No | Treg: FOXP3+; effector T cells: CD3+ + CD4+ or CD8+ | FOXP3+ cells were found in the large and small intestine as early as 23 weeks GA. There was no change in the ratio of FOXP3+ to CD4+ or CD8+ cells with postnatal exposure. CD3+, CD4+, CD8+ and FOXP3+ cells were decreased in NEC patients, but present in same ratios as the other diseases. |
Weitkamp [7] | 2013 | Case control | Human | 48 total, 18 cases, 30 controls | No | Fresh ileal tissue samples from NEC patients and non-NEC intestinal surgical patients matched for GA. LPMCs and Tregs were isolated. T cell suppression assay and PCR on total ileal RNA performed. | No | Yes: on remnant surgical intestinal tissue | Treg: CD4+ + Cd25+ + FOXP3+ + CD127low + CD45RO; effector T cells: CD4+ or CD8+ | Proportions of Tregs to CD4+ or CD8+ T cells were lower in ileum of NEC patients. Absolute Treg number was decreased in NEC patients. Treg proportions increased after NEC healing. |
Dingle [6] | 2013 | Experimental | Sprague Dawley rat pup | 134 total | Yes: formula fed, starved 12 h after birth, hypoxia | Rats were divided into groups: dam-fed; NEC induction; NEC induction + Treg supplementation; NEC induction + saline supplement; NEC induction + active Treg supplementation; NEC induction + active Teff supplementation. | Yes: terminal ileum HE staining | Yes: on spleen, thymus, mesenteric lymph node and terminal ileum | Treg: CD3+ + CD4+ + FOXP3+; effector T cells: CD3+ + CD4+ or CD8+ | The Treg frequency in the ileum was significantly lower in NEC-induced rats. NEC-induced rats had lower NEC incidence after Treg transfer. Levels of ileal Tregs were higher towards normal after Treg transfer. CD25 expression and T cell maturation occurred in rats after the Teff transfer. |
Egan [17] | 2016 | Experimental | Wild type; RAG−/−; IL-17-GFP; RORyt-GFP mice | 170 total | Yes: formula fed, hypoxia, NEC patient enteric bacteria supplementation | Enterocytes incubated with LPS, IL-17A or vehicle for 6 h. ELISA and immunoblots performed. | Yes: ileum HE staining | Yes, on lamina propria cells | Treg: CD4+ + FOXP3+; Th17 cells: CD4+ + RORγt+ | RORγt+ T cells were increased and FOXP3+ T cells were decreased after NEC induction compared to wild-type mice. T cell deficient (RAG−/−) mice were protected from developing NEC. |
Niño [19] | 2017 | Experimental | Wild-type mice, enterocyte culture | 120 total | Yes: formula fed, hypoxia, NEC patient enteric bacteria supplementation | Enterocytes treated with IL-17A or vehicle for 6 h. Immunohistochemistry performed. Mice were divided into groups: dam-fed; dam-fed + ATRA supplement; NEC induction; NEC induction + ATRA supplement; NEC induction + Treg depletion. | Yes: terminal ileum HE staining | Yes: on lamina propria cells | Treg: CD4+ + FOXP3+; Th17 cells: CD4+ + IL-17+ | Th17 cell activation and IL-17 expression was increased in NEC mice. Treg depletion lead to increased intestinal damage after NEC induction. ATRA preserved levels of Tregs in NEC-induced mice. ATRA decreased Th17 cell induction and IL-17 expression in NEC-induced mice. |
Pang [20] | 2018 (June) | Case control | Human | 30 total, 15 cases, 15 controls | No | Blood samples from infants displaying clinical NEC symptoms, included after surgical procedure. Non-NEC controls matched for BW, GA and sex. RT-PCR and cytokines ELISA performed. | No | Yes: on blood | Treg: CD4+ + FOXP3+; Th17 cells: CD4+ + RORγt+ | Monocytes from NEC infants had higher TLR4 expression. CD4+ T cells of NEC patients had higher RORC and lower FOXP3 transcription than controls, and expression of IL-17 was increased in patients. |
Pang [11] | 2018 (October) | Case control | Human | 30 total, 15 cases, 15 controls | No | Blood samples from infants displaying clinical NEC symptoms, included after surgical procedure. Non-NEC controls matched for BW, GA and sex. RT-PCR and cytokines ELISA performed. | No | Yes: on blood | Treg: CD3+ + CD4+ + CD25+ + FOXP3+; Th17 cells: CD3+ + CD4+ + IL-17+ | Treg frequency was significantly lower in NEC patients. Tregs of NEC infants have reduced expression of Treg related genes. The frequency of IL-17+ CD4+ T cells and level of IL-17 was significantly higher in NEC infants. |
Ma [24] | 2019 | Experimental and case control | Wild-type mice, human | Mouse: 83 total Human: 157 total, 77 cases, 80 controls | Mouse: Yes: formula fed, hypoxia, NEC patient enteric bacteria supplementation Human: No | Mouse: Mice divided into groups: dam-fed; NEC induction; NEC induction + anti-IL6R supplement. Cytokine ELISAs and total protein Western blots performed. Human: Blood samples from infants diagnosed with NEC and BW, GA and sex matched control neonates. Tregs and CCR9+ CD4+ T cells isolated. Treg polarization, T cell proliferation and suppression assays performed. RT-PCR performed on total RNA from CCR9+ CD4+ T cells. | Mouse: Yes: ileum HE staining Human: No | Mouse: Yes: on ileum Human: Yes: on blood | Mouse: Treg: CD4+ + FOXP3+; Th17 cells: CD4+ + IL-17+ Human: Treg: CD4+ + FOXP3+; Th17 cells: CD4+ + RORγt+ | Mouse: Levels of Th17 cells and IL-17+ Tregs increased and Treg levels decreased after NEC induction compared to controls. Frequency of circulating CCR9+ IL-17+ Tregs increased after NEC inductions. Increased level of circulating CCR9+ IL-17+ Tregs correlated negatively to severity of intestinal damage. Human: Monocytes from NEC infants had higher TLR4 expression. CD4+ T cells of NEC patients had higher RORC and lower FOXP3 transcription than controls, and expression of IL-17 was increased in patients. |
Ma [28] | 2020 | Experimental | Wild-type mice | 60 total | Yes: Formula fed, hypoxia, cold stress | Mice divided into groups: dam-fed; NEC induction; NEC induction + melatonin supplement; NEC induction + saline supplement; NEC induction + melatonin supplement + Treg ablation; NEC induction + saline supplement + Treg ablation. | Yes: ileum HE staining | Yes: on lamina propria mononuclear cells | Treg: CD4+ + FOXP3+; Th17 cells: CD4+ + IL-17+ | Levels of Th17 cells increased and levels of Tregs decreased after NEC induction. Melatonin supplementation during NEC induction normalized Th17 cell and Treg levels and decreased NEC incidence. NEC protection by melatonin was impaired after Treg ablation. |
3.3. Immune Modulation in NEC
Author | Year | Study Design | Species | Sample Size | NEC Induction | Methods | Histological NEC Score | Flow Cytometry | T Cell Markers | Most Relevant Findings |
---|---|---|---|---|---|---|---|---|---|---|
Schulz [29] | 2015 | Experimental | Wild-type mice: HO1−/−; HO1+/− | 51 total | Yes: formula fed, hypoxia | HO1+/− mice were injected with wild-type Tregs. | Yes: intestine HE staining | Yes, on ileum | Treg: CD4+ + CD25+ + FOXP3+; effector T cells: CD4+ | Treg frequency was decreased in NEC induced mice. High Treg/effector T cell ratio was associated with attenuated intestinal damage. Treg transfer during NEC induction reduced intestinal damage scores and NEC incidence. |
Chen [31] | 2020 | Experimental | Sprague Dawley rats | 58 total | Yes: formula fed, starved 12 h after birth, hypoxia | BM-MSCs transfected with PHD2 or GFP silencing lentivirus. Cytokine assay on conditioned medium. Conditioned medium was supplied to rats. Cytokine arrays, qPCR and Western blot performed. | Yes: terminal ileum HE staining | Yes, on enterocyte culture and rat mesenteric lymph nodes | Treg: CD4+ + FOXP3+ | PHD2 knockdown reduced NEC incidence and ileal damage. PHD2 knockdown increased number of FOXP3 Tregs in the mesenteric lymph nodes. PHD2 knockdown BM-MSCs produced more anti-inflammatory and Treg inducing cytokines. |
3.4. The Role of Milk on NEC and Tregs
Author | Year | Study Design | Species | Sample Size | NEC Induction | Methods | Histological NEC Score | Flow Cytometry | T Cell Markers | Most Relevant Findings |
---|---|---|---|---|---|---|---|---|---|---|
Li [38] | 2020 | Experimental | Preterm piglets | 74 total | No | Piglets divided in groups: 4 day colostrum fed; 4 days formula fed. After day 4, piglets again divided in groups: continuation of previous diet until day 9; switched diet until day 9; euthanasia. Cytokine ELISAs performed before euthanasia. qPCR performed for mucosal gene expression. | Yes: proximal, middle and distal smallintestine HE staining | Yes: on arterial blood | Treg: CD4+ + CD25+ + FOXP3+; effector T cells: CD3+ + CD4+ or CD8+ | Pigs fed colostrum for 4 days had lower NEC incidence and less severe intestinal lesions. After 9 days, NEC incidences were similar among all the different groups. Treg frequency was higher in groups fed colostrum at any point compared to pigs fed formula only. |
Xu [40] | 2013 | Experimental | Sprague Dawley rats | 90 total | Yes: formula fed, hypoxia, cold stress | Rats divided into groups: dam-fed; NEC induction; NEC induction + GD3 supplement. Cytokine array and FOXP3 immunoblot performed. FOXP3 immunofluorescence performed on ileum. | Yes: distal ileum HE staining | No | Treg: FOXP3+ | GD3 supplementation reduced NEC incidence and severity scores. Levels of inflammatory cytokines were increased in NEC rats, but normalized after GD3 supplementation. FOXP3 expression was lower in the lamina propria of NEC rats. FOXP3 expression increased after GD3 supplementation. |
Akin [43] | 2014 | Randomised clinical trial | Human | 50 total, 25 lactoferrin prophylaxis, 25 placebo | No | Neonates with VLBM or GA less than 32 randomised to bLF or placebo groups. bLF and placebo supplemented in milk or formula once daily for entire hospital stay. Blood samples obtained at birth and discharge. | No | Yes: on blood | Treg: CD4+ + CD25+ + FOXP3+ | In control patients, 20% of neonates developed NEC. In the bLF-treated group, none of the neonates developed NEC. No significant differences were found in Treg levels between groups. Level of Tregs increased significantly between birth and discharge in bLF-treated infants. |
3.5. The Effect of Probiotics on Tregs
Author | Year | Study Design | Species | Sample Size | NEC Induction | Methods | Histological NEC Score | Flow Cytometry | T Cell Markers | Most Relevant Findings |
---|---|---|---|---|---|---|---|---|---|---|
Liu [5] | 2013 | Experimental | Sprague Dawley rats | 180 total | Yes: formula fed, starved 12 h after birth, hypoxia | Rats divided into groups: dam-fed; dam-fed + LR17938 supplement; NEC induction; NEC induction + LR17938 supplement. CD3 immunohistochemistry performed. | Yes: terminal ileum HE staining | Yes: on spleen, thymus and mesenteric lymph node | Treg: CD3+ + CD4+ + FOXP3+; effector T cells: CD3+ + CD4+ or CD8+ | Treg percentage increased during first days of life in dam-fed rats. Treg percentages were significantly lower in NEC rats. Treg percentage and survival rates were higher in NEC rats after LR17938 supplementation. |
Liu [53] | 2014 | Experimental | Wild-type mice | 99 total | Yes: formula fed, 12 h starvation, hypoxia, cold stress | Mice divided into groups: dam-fed; dam-fed + LR17938 supplement; NEC induction; NEC induction + LR17938 supplement. | Yes: intestine HE staining | Yes: on ileum | Treg: CD4+ + FOXP3+; activated effector T cells: CD4+ + CD44+ + CD4RBlo | Treg frequency decreased and effector T cell frequency increased in ileum and mesenteric lymph nodes of NEC mice. Treg and effector T cell levels remained the same as controls after LR17938 treatment. |
Hoang [54] | 2018 | Experimental | Mice: wild type; TLR−/− | 106 total | Yes, formula fed, hypoxia, cold stress | Mice divided into groups: dam-fed; NEC induction; NEC induction + anti-IL6R supplement. Cytokine ELISAs and total protein Western blots performed. | Yes: ileum HE staining | Yes: on ileum | Treg: CD4+ + FOXP3+; Th17 cells: CD4+ + IL-17+ | Levels of Th17 cells and IL-17+ Tregs increased and Treg levels decreased after NEC induction compared to controls. Frequency of circulating CCR9+ IL-17+ Tregs increased after NEC induction. Increased level of circulating CCR9+ IL-17+ Tregs correlated negatively to severity of intestinal damage. |
Qazi [55] | 2020 | Randomised control trial | Human | 163 total 134 ELBW, 29 term. | No | Neonates with ELBW randomised into LR17938 or placebo supplement groups. Blood taken at day 14, day 28 at PMW 36 + 0. PBMC isolated. | No | Yes: on blood | Treg: CD4+ + CD25+ + FOXP3+ + CD127+; effector T cells: CD4+ or CD8+ | Percentages of total and viable lymphocytes were significantly lower in ELBW neonates at 14 DOL. ELBW infants have a reduced Tbet/GATA3 ratio and Helios level in Tregs at both 14 and 28 DOL. LR17938 supplementation had no impact on the T cell proportions. |
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Zuiderwijk, M.O.; van der Burg, M.; Bekker, V.; Schoenaker, M.H.D. Regulatory T Cells in Development and Prediction of Necrotizing Enterocolitis in Preterm Neonates: A Scoping Review. Int. J. Mol. Sci. 2022, 23, 10903. https://doi.org/10.3390/ijms231810903
Zuiderwijk MO, van der Burg M, Bekker V, Schoenaker MHD. Regulatory T Cells in Development and Prediction of Necrotizing Enterocolitis in Preterm Neonates: A Scoping Review. International Journal of Molecular Sciences. 2022; 23(18):10903. https://doi.org/10.3390/ijms231810903
Chicago/Turabian StyleZuiderwijk, Mara O., Mirjam van der Burg, Vincent Bekker, and Michiel H. D. Schoenaker. 2022. "Regulatory T Cells in Development and Prediction of Necrotizing Enterocolitis in Preterm Neonates: A Scoping Review" International Journal of Molecular Sciences 23, no. 18: 10903. https://doi.org/10.3390/ijms231810903