Epigenetic immune cell counting is a DNA (de)methylation-based technique which can be used to quantify lymphocyte subsets on dried blood spots (DBS). The foregoing techniques allow for a... Show moreEpigenetic immune cell counting is a DNA (de)methylation-based technique which can be used to quantify lymphocyte subsets on dried blood spots (DBS). The foregoing techniques allow for a retrospective investigation of immune cell profiles in newborns. In this study, we used this technique for determining lymphocyte subcounts as a potential biomarker for necrotizing enterocolitis (NEC). We investigated whether this technique can be implemented in the field of neonatology, by testing whether regulatory T cell (Treg) levels are pre-existently low in preterms with NEC. Newborn screening (NBS) cards from 32 preterms with NEC and 32 age- and weight-matched preterm controls, and 60 healthy term newborns, were analyzed. Relative and absolute cell counts were determined for CD3+, CD4+, CD8+, Th17, and Treg T cells. For both relative and absolute cell counts of CD3+, CD4+, CD8+, and Th17 T cells, significant differences were found between healthy term controls and both preterm groups, but not between preterm groups. For Tregs, no significant differences were found in either relative or absolute counts between any of the newborn groups. This study demonstrates the principle of epigenetic immune cell counting to analyze lymphocyte subsets in preterm neonates. Show less
Zuiderwijk, M.O.; Burg, M. van der; Bekker, V.; Schoenaker, M.H.D. 2022
Necrotizing enterocolitis (NEC) is a leading cause of mortality in premature infants. However, the pathophysiology and influence of regulatory T cells (Tregs) have not been sufficiently elucidated.... Show moreNecrotizing enterocolitis (NEC) is a leading cause of mortality in premature infants. However, the pathophysiology and influence of regulatory T cells (Tregs) have not been sufficiently elucidated. We performed a scoping review to investigate current knowledge on the influence of Tregs in NEC, and to investigate the predictive value of Treg number in NEC development. Pubmed, Embase, Prospero and Cochrane Library were searched during December 2020. Primary research articles discussing Tregs and NEC development written in English were selected. Two reviewers screened title and abstract for relevance, after which full-text screening was performed. A total of 20 articles were selected-13 of the articles discussed studies performed in animal models, while 8 used human neonate data. One study discussed both animal and human data. It was shown that after NEC diagnosis or induction, Treg levels were decreased while Th17 levels were increased. No studies were found which investigated the predictive value of Treg number in NEC development. A reduced Treg level is found in animals and neonates with NEC. The question remains whether this effect is a factor on the causal pathway of NEC development or a bystander effect. Future research focusing on the pathophysiological timeline of NEC and the involvement of Tregs is required for better understanding of this disease. Show less
Mensink, M.; Tran, T.N.M.; Zaal, E.A.; Schrama, E.; Berkers, C.R.; Borst, J.; Kivit, S. de 2022
CD4(+) conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases... Show moreCD4(+) conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases. The opposing activities of Tconvs and Tregs depend on the stage of the immune response and their environment, with an orchestrating role for cytokine- and costimulatory receptors. Nutrient availability also impacts T-cell functionality via metabolic and biosynthetic processes that are largely unexplored. Many data argue that costimulation by Tumor Necrosis Factor Receptor 2 (TNFR2) favors support of Treg over Tconv responses and therefore TNFR2 is a key clinical target. Here, we review the pertinent literature on this topic and highlight the newly identified role of TNFR2 as a metabolic regulator for thymus-derived (t)Tregs. We present novel transcriptomic and metabolomic data that show the differential impact of TNFR2 on Tconv and tTreg gene expression and reveal distinct metabolic impact on both cell types. Show less
Mensink, M.; Tran, T.N.M.; Zaal, E.A.; Schrama, E.; Berkers, C.R.; Borst, J.; Kivit, S. de 2022
CD4+ conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases.... Show moreCD4+ conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases. The opposing activities of Tconvs and Tregs depend on the stage of the immune response and their environment, with an orchestrating role for cytokine- and costimulatory receptors. Nutrient availability also impacts T-cell functionality via metabolic and biosynthetic processes that are largely unexplored. Many data argue that costimulation by Tumor Necrosis Factor Receptor 2 (TNFR2) favors support of Treg over Tconv responses and therefore TNFR2 is a key clinical target. Here, we review the pertinent literature on this topic and highlight the newly identified role of TNFR2 as a metabolic regulator for thymus-derived (t)Tregs. We present novel transcriptomic and metabolomic data that show the differential impact of TNFR2 on Tconv and tTreg gene expression and reveal distinct metabolic impact on both cell types. Show less
Mensink, M.; Tran, T.N.M.; Zaal, E.A.; Schrama, E.; Berkers, C.R.; Borst, J.; Kivit, S. de 2022
CD4(+) conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases... Show moreCD4(+) conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases. The opposing activities of Tconvs and Tregs depend on the stage of the immune response and their environment, with an orchestrating role for cytokine- and costimulatory receptors. Nutrient availability also impacts T-cell functionality via metabolic and biosynthetic processes that are largely unexplored. Many data argue that costimulation by Tumor Necrosis Factor Receptor 2 (TNFR2) favors support of Treg over Tconv responses and therefore TNFR2 is a key clinical target. Here, we review the pertinent literature on this topic and highlight the newly identified role of TNFR2 as a metabolic regulator for thymus-derived (t)Tregs. We present novel transcriptomic and metabolomic data that show the differential impact of TNFR2 on Tconv and tTreg gene expression and reveal distinct metabolic impact on both cell types. Show less
Background: Inflammatory stimuli induced by NF-kB drive atherosclerotic lesion formation. The epigenetic P300/CBP associated factor (PCAF) post-transcriptionally acetylates FoxP3, which is required... Show moreBackground: Inflammatory stimuli induced by NF-kB drive atherosclerotic lesion formation. The epigenetic P300/CBP associated factor (PCAF) post-transcriptionally acetylates FoxP3, which is required for regulatory T-cell (Treg) differentiation and immune modulation. We hypothesize that PCAF deficiency affects atherosclerosis via regulation of regulatory Tregs.Method: ApoE3*Leiden (n = 13) and ApoE3*LeidenxPCAF(-/-) (n = 13) were fed a high-fat diet (HFD) containing 1.25% cholesterol. Systemic FoxP3(+) T cells were measured every 4 weeks by flow cytometry (n = 6). After 5-months of HFD, mice were euthanized, and hearts and blood were collected. IL-6 and TNF alpha concentrations were measured in plasma to identify systemic inflammatory responses. Compositional and morphometrical analyses were performed on the atherosclerotic lesions in the aortic sinuses.Results: After 5 months of HFD, plasma cholesterol concentrations were not different for ApoE3*LeidenxPCAF(-/-) compared to ApoE3*Leiden mice. Expression of FoxP3 by systemic CD4(+) T cells decreased 1.8 fold in ApoE3*LeidenxPCAF(-/-) after 5 months HFD and remained significantly reduced after 5 months of HFD. Systemic TNF alpha and IL-6 concentrations were comparable, whereas the atherosclerotic lesion size in ApoE3*LeidenxPCAF(-/-) mice was increased by 28% compared to ApoE3*Leiden mice. In atherosclerotic lesions, no differences were observed in macrophage differentiation or VSMC content, although a small increase in collagen was identified.Conclusion: Our data show that PCAF deficiency resulted in a decrease in circulatory FoxP3(+) regulatory T cells and ameliorated atherosclerotic lesions with no differences in systemic inflammation or macrophage differentiation in the atherosclerotic lesions. This suggests that PCAF regulates atherosclerosis via modulation of FoxP3(+) regulatory T cell differentiation. Show less
Craenmehr, M.H.C.; Heidt, S.; Eikmans, M.; Claas, F.H.J. 2016
