Neonatal T-cell maturation and homing receptor responses to Toll-like receptor ligands differ from those of adult naive T cells: relationship to prematurity

Crespo, Maricruz; Martinez, Denise; Cerissi, Adam; Rivera-Reyes, Brenda M.; Bernstein, Helene B.; Lederman, Michael M.; Sieg, Scott F.; Luciano, Angel A.

doi:10.1038/pr.2011.26

Cited by 31 publications

(25 citation statements)

References 35 publications

(35 reference statements)

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“…Despite the important role of T regs in mediating immunosuppression in adult patients with severe sepsis , to what extent T regs contribute to the distinct susceptibility to infection of preterm infants is still unknown .…”

Section: Introductionmentioning

confidence: 99%

Regulatory T cell frequencies are increased in preterm infants with clinical early-onset sepsis

Pagel

Hartz

Figge

et al. 2016

Clinical and Experimental Immunology

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SummaryThe predisposition of preterm neonates to invasive infection is, as yet, incompletely understood. Regulatory T cells (T regs ) are potential candidates for the ontogenetic control of immune activation and tissue damage in preterm infants. It was the aim of our study to characterize lymphocyte subsets and in particular CD41 CD25 1 forkhead box protein 3 (FoxP3) 1 T regs in peripheral blood of well-phenotyped preterm infants (n 5 117; 23 1 0 -36 1 6 weeks of gestational age) in the first 3 days of life in comparison to term infants and adults. We demonstrated a negative correlation of T reg frequencies and gestational age. T regs were increased in blood samples of preterm infants compared to term infants and adults. Notably, we found an increased T reg frequency in preterm infants with clinical early-onset sepsis while cause of preterm delivery, e.g. chorioamnionitis, did not affect T reg frequencies. Our data suggest that T regs apparently play an important role in maintaining maternal-fetal tolerance, which turns into an increased sepsis risk after preterm delivery. Functional analyses are needed in order to elucidate whether T regs have potential as future target for diagnostics and therapeutics.

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Section: Introductionmentioning

confidence: 99%

Regulatory T cell frequencies are increased in preterm infants with clinical early-onset sepsis

Pagel

Hartz

Figge

et al. 2016

Clinical and Experimental Immunology

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“…Activation of the human fetal immune system and the ensuing fetal inflamma-tory response are associated with premature termination of pregnancy and severe neonatal morbidity (5,6). Activated T cells and reduced suppressive Treg activity are evident during fetal inflammation (7)(8)(9)(10), and maternal-reactive fetal Th1 cells are implicated in the pathophysiology of preterm birth (PTB) (11). Animal models of intrauterine inflammation identify the fetal intestine as a potential site for the initiation of immune activation (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

CD161 contributes to prenatal immune suppression of IFN-γ–producing PLZF+ T cells

Halkias¹,

Rackaityte²,

Hillman³

et al. 2019

Journal of Clinical Investigation

109

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BACKGROUND. While the human fetal immune system defaults to a program of tolerance, there is a concurrent need for protective immunity to meet the antigenic challenges encountered after birth. Activation of T cells in utero is associated with the fetal inflammatory response, with broad implications for the health of the fetus and of the pregnancy. However, the characteristics of the fetal effector T cells that contribute to this process are largely unknown. METHODS.We analyzed primary human fetal lymphoid and mucosal tissues and performed phenotypic, functional, and transcriptional analysis to identify T cells with proinflammatory potential. The frequency and function of fetal-specific effector T cells was assessed in the cord blood of infants with localized and systemic inflammatory pathologies and compared with that of healthy term controls. RESULTS.We identified a transcriptionally distinct population of CD4 + T cells characterized by expression of the transcription factor promyelocytic leukemia zinc finger (PLZF). PLZF + CD4 + T cells were specifically enriched in the fetal intestine, possessed an effector memory phenotype, and rapidly produced proinflammatory cytokines. Engagement of the C-type lectin CD161 on these cells inhibited TCR-dependent production of IFN-γ in a fetal-specific manner. IFN-γ-producing PLZF + CD4 + T cells were enriched in the cord blood of infants with gastroschisis, a natural model of chronic inflammation originating from the intestine, as well as in preterm birth, suggesting these cells contribute to fetal systemic immune activation. CONCLUSION.Our work reveals a fetal-specific program of protective immunity whose dysregulation is associated with fetal and neonatal inflammatory pathologies. cells in the development of protective immunity and their contribution to perinatal immune dysregulation is not known.Here, we performed a detailed analysis of human CD4 + T cell phenotype and function in fetal lymphoid and mucosal tissues. We show that Vα7.2 -PLZF + TCR-αβ + CD4 + T cells (herein referred to as PLZF + CD4 + T cells) specifically accumulated in the fetal intestine and were absent from the adult. Fetal PLZF + CD4 + T cells represent a transcriptionally unique subset of CD4 + T cells that are distinct from either innate-like, semi-invariant Va7.2 + T cells or PLZF -CD4 + T cells. Consistent with a primarily T effector memo-memory originates in utero. Innate-like T cells with rapid effector functions, such as γδ T cells, mucosa-associated invariant T (MAIT) cells, and innate-like NKT cells, are also present in fetal tissues (23)(24)(25). Promyelocytic leukemia zinc finger (PLZF), a transcriptional regulator that directs the differentiation of innate-like T cells (26,27), is widely expressed in human immune cells and is commonly associated with expression of CD161, a C-type lectin receptor (28). The human fetal thymus uniquely produces a subset of CD4 + T cells, distinct from NKT cells and MAIT cells, that expresses the transcription factor PLZF (29). However, the role of fetal PLZF ...

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“…In fact, previous studies have shown an increase of activation/memory markers (CD45RO, CD69, HLA-DR, CD25) from total cord blood (CB) CD4 + cells in early preterm neonates (27–31w) exposed to chorio compared to healthy full term neonates [9,10]. Interestingly, fetal sheep exposed to chorio have inflammatory changes in many organ systems both in utero and after birth [11,12].…”

Section: Introductionmentioning

confidence: 99%

Effect of chorioamnionitis on regulatory T cells in moderate/late preterm neonates

et al. 2015

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Regulatory T-cells (Treg) have a protective role for the control of immune activation and tissue damage. The effects of chorioamnionitis (chorio) on Treg in moderate/late preterm newborns are not known. We hypothesized that infants exposed to chorio would have decreased Treg frequency and/or function. We isolated mononuclear cells from adult peripheral blood and cord blood from term and moderate/late preterm infants who were classified for severity of chorio exposure. Mononuclear cells were analyzed by flow cytometry for Treg frequency and phenotype. Treg suppression of activation of conventional T-cells (Tcon) was also quantified. Treg frequencies were similar in all groups of neonates, but lower than that found in adults. Newborn Treg had a naïve phenotype, with decreased levels of CD45RO, HLA-DR, CD39 and TIGIT compared to adult Treg and chorio did not affect the phenotype. Treg from preterm newborns exposed to severe chorio had higher expression of Ki67 compared to the other groups. Treg from preterm newborns were less suppressive than Treg from adults or term, and the level of suppression was reduced with severe chorio. Relative to term, Treg frequency and phenotype were not affected by prematurity and chorio but their functionality was decreased. Lower Treg activity may contribute to inflammation in newborns that is often associated with chorioamnionitis.

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Neonatal T-cell maturation and homing receptor responses to Toll-like receptor ligands differ from those of adult naive T cells: relationship to prematurity

Cited by 31 publications

References 35 publications

Regulatory T cell frequencies are increased in preterm infants with clinical early-onset sepsis

Regulatory T cell frequencies are increased in preterm infants with clinical early-onset sepsis

CD161 contributes to prenatal immune suppression of IFN-γ–producing PLZF+ T cells

Effect of chorioamnionitis on regulatory T cells in moderate/late preterm neonates

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