Multivariate Analysis Using High Definition Flow Cytometry Reveals Distinct T Cell Repertoires between the Fetal–Maternal Interface and the Peripheral Blood

Neller, Michelle A.; Santner-Nanan, Brigitte; Brennan, Rebekah; Hsu, Peter; Joung, Steven; Nanan, Ralph; Burrows, Scott R.; Miles, John J.

doi:10.3389/fimmu.2014.00033

Cited by 7 publications

(6 citation statements)

References 21 publications

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“…However, there is compelling data suggesting that changes in percentages of Treg cells within CD4 + cells play a central role in many immune-mediated pathologies 40–43 . In line with this, our own group has shown reduced percentages in maternal Tregs to be a feature of altered immunity in preeclampsia 4,44,45 . Hence, differences in percentages of offspring Treg cells described in this study between the preeclampsia and non-preeclampsia groups seems highly relevant.…”

Section: Discussionsupporting

confidence: 62%

Decreased maternal serum acetate and impaired fetal thymic and regulatory T cell development in preeclampsia

Hu¹,

Eviston²,

Hsu³

et al. 2019

Nat Commun

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102

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Maternal immune dysregulation seems to affect fetal or postnatal immune development. Preeclampsia is a pregnancy-associated disorder with an immune basis and is linked to atopic disorders in offspring. Here we show reduction of fetal thymic size, altered thymic architecture and reduced fetal thymic regulatory T (Treg) cell output in preeclamptic pregnancies, which persists up to 4 years of age in human offspring. In germ-free mice, fetal thymic CD4 + T cell and Treg cell development are compromised, but rescued by maternal supplementation with the intestinal bacterial metabolite short chain fatty acid (SCFA) acetate, which induces upregulation of the autoimmune regulator (AIRE), known to contribute to Treg cell generation. In our human cohorts, low maternal serum acetate is associated with subsequent preeclampsia, and correlates with serum acetate in the fetus. These findings suggest a potential role of acetate in the pathogenesis of preeclampsia and immune development in offspring.

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Section: Discussionsupporting

confidence: 62%

Decreased maternal serum acetate and impaired fetal thymic and regulatory T cell development in preeclampsia

Hu¹,

Eviston²,

Hsu³

et al. 2019

Nat Commun

Self Cite

102

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“…In contrast, the repertoire of effector Treg cells of PBMC was not skewed in the 3rd trimester. A previous study showed that TRBV repertoires of total Treg cells differ in PBMC and decidua in the 3rd trimester ( 22 ). Our data support this finding.…”

Section: Discussionmentioning

confidence: 99%

“…T cell receptor β variable (TRBV) repertoires of total Treg cells in peripheral blood and decidua were not significantly different between preeclampsia and normal pregnancy (22). Thus, how Treg cells relate to the development of preeclampsia remains unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Previous reports suggested that systemic and local maldistribution and dysfunction of Treg cells could be one of the etiologies of miscarriage and preeclampsia ( 16 – 21 ). T cell receptor β variable (TRBV) repertoires of total Treg cells in peripheral blood and decidua were not significantly different between preeclampsia and normal pregnancy ( 22 ). Thus, how Treg cells relate to the development of preeclampsia remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Clonally Expanded Decidual Effector Regulatory T Cells Increase in Late Gestation of Normal Pregnancy, but Not in Preeclampsia, in Humans

et al. 2018

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Background: Regulatory T (Treg) cells are necessary for the maintenance of allogenic pregnancy. However, the repertoire of effector Treg cells at the feto-maternal interface in human pregnancy remains unknown. Our objective was to study T cell receptor (TCR) repertoires of Treg cells during pregnancy compared to normal and complicated pregnancies.Methods:Paired samples of peripheral blood and decidua in induced abortion and miscarriage cases were obtained from consenting patients. CD4+CD25+CD127low/−CD45RA− effector Treg cells were single-cell sorted from mononuclear cells. cDNAs of complementarity determining region 3 (CDR3) in TCRβ were amplified from the single cells by RT-PCR and the sequences were analyzed. The TCRβ repertoires were determined by amino acid and nucleotide sequences. Treg cells were classified into clonally expanded and non-expanded populations by CDR3 sequences.Results: We enrolled nine induced abortion cases in the 1st trimester, 12 cases delivered without complications in the 3rd trimester, 11 miscarriages with abnormal chromosomal karyotyped embryo, seven miscarriages with normal chromosomal karyotyped embryo, and seven cases of preeclampsia [median gestational week (interquartile range): 7 (7–9), 39 (38–40), 9 (8–10), 8 (8–10), and 34 (32–37), respectively]. The frequency of clonally expanded populations of effector Treg cells increased in decidua of 3rd trimester cases compared to 1st trimester cases [4.5% (1.4–10.8%) vs. 20.9% (15.4–28.1%), p < 0.001]. Clonally expanded Treg cells were rarely seen in peripheral blood. The ratio of clonally expanded populations of decidual effector Treg cells in miscarriages with abnormal and normal embryos was not significantly different compared with that in 1st trimester normal pregnancy. Interestingly, clonally expanded populations of effector Treg cells decreased in preeclampsia compared with that in 3rd trimester normal pregnancy [9.3% (4.4–14.5%) vs. 20.9% (15.4–28.1%), p = 0.003]. When repertoires in previous pregnancy and subsequent pregnancy were compared, some portions of the repertoire were shared.Conclusion: TCR repertoires of decidual effector Treg cells are skewed in the 3rd trimester of normal pregnancy. Failure of clonal expansion of populations of decidual effector Treg cells might be related to the development of preeclampsia.

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“…Previous studies on decidua tissue taken from term placenta samples show that Tregs undergo clonal expansion throughout pregnancy, of note this cannot be detected in the peripheral blood Treg ( 26), but peripheral blood Treg numbers increase in human pregnancies as gestation progresses. Our observation that the CD4Tconv compartment is similar between the PB and endometrium, whereas Treg have greater significant phenotypic differences, suggests Treg tissue specificity, this was observed by a study analysing the T cell receptor beta variable (TRBV) repertoire that found most variation in the Treg population between cells derived from the blood or decidua (27). IFN was identified as the most upregulated gene in Treg from parous women.…”

Section: Discussionmentioning

confidence: 56%

Characterisation of peri-implantation endometrial Treg and identification of an altered phenotype in recurrent pregnancy loss

Granne

Shen

Rodriguez-Caro

et al. 2021

Preprint

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Recurrent Pregnancy Loss (RPL) affects 2-4% of couples, and with increasing numbers of pregnancy losses the risk of miscarrying a euploid pregnancy is increased, suggesting RPL is a pathology distinct from sporadic miscarriage that is due largely to lethal embryonic aneuploidy. There are a number of conditions associated with RPL including unspecified ‘immune’ pathologies, one of the strongest candidates for dysregulation remains T regulatory cells as depletion in the very early stages of pregnancy in mice leads to pregnancy loss.Human endometrial Treg and conventional CD4T cells were isolated during the peri-implantation period of the menstrual cycle in normal women. We identified an endometrial Treg transcriptomic signature and validated an enhanced regulatory phenotype compared to peripheral blood Treg. Parous women had an altered endometrial Treg transcriptome compared to nulliparity, indicating acquired immunity memory of pregnancy within the Treg population, by comparison endometrial conventional CD4T cells were not altered. We compared primary and secondary RPL to nulliparous or parous controls respectively. Both RPL subgroups displayed differentially expressed Treg gene transcriptomes compared to controls. We found increased cell surface S1PR1 and decreased TIGIT protein expression by Treg in primary RPL, confirming the presence of altered Treg in the peri-implantation RPL endometrium.

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Multivariate Analysis Using High Definition Flow Cytometry Reveals Distinct T Cell Repertoires between the Fetal–Maternal Interface and the Peripheral Blood

Cited by 7 publications

References 21 publications

Decreased maternal serum acetate and impaired fetal thymic and regulatory T cell development in preeclampsia

Decreased maternal serum acetate and impaired fetal thymic and regulatory T cell development in preeclampsia

Clonally Expanded Decidual Effector Regulatory T Cells Increase in Late Gestation of Normal Pregnancy, but Not in Preeclampsia, in Humans

Characterisation of peri-implantation endometrial Treg and identification of an altered phenotype in recurrent pregnancy loss

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