CD8 + T Cells from Human Neonates Are Biased toward an Innate Immune Response

Galindo‐Albarrán, Ariel; López-Portales, Óscar Humberto; Gutiérrez-Reyna, Darely Y.; Rodríguez-Jorge, Otoniel; Sánchez-Villanueva, José Antonio; Ramírez-Pliego, Oscar; Bergon, Aurélie; Loriod, Béatrice; Holota, Hélène; Imbert, Jean; Hernández-Mendoza, Armando; Ferrier, Pierre; Pau, Enrique Carrillo de Santa; Valencia, Alfonso; Spicuglia, Salvatore; Santana, María Angélica

doi:10.1016/j.celrep.2016.10.056

Cited by 59 publications

(82 citation statements)

References 43 publications

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“…Butyrate is also able to direct epigenetic gene modification by acting on HDAC (35). Given the importance of epigenetic mechanisms involved in regulating development and function of infant T cells (32, 75), it is interesting to speculate regarding their permissiveness to circulating bacterial metabolites derived from the infant GIM. A direct effect of LPS on enriched or purified human and murine T cells in vitro has been previously described (76).…”

Section: Discussionmentioning

confidence: 99%

“…As demonstrated in mice and humans, infant T cells are capable of producing IFN-γ in response to infection, but this may be skewed in timing (too early) and in magnitude (too weak) as compared to adult T cells (28). These developmental differences may be modulated by intrinsic or extrinsic mechanisms and include epigenetic hypermethylation of the IFN-γ promoter (29), increased T cell receptor (TCR) activation threshold regulated by miRNA (30), inhibition by Tregs (31), skew toward innate functional profile (32), insufficient facilitation by infant antigen-presenting cells (33), or by metabolites of the GIM (34, 35). …”

Section: Introductionmentioning

confidence: 99%

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Gastrointestinal Microbiome Dysbiosis in Infant Mice Alters Peripheral CD8+ T Cell Receptor Signaling

González‐Pérez

Lamousé-Smith

2017

Front. Immunol.

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We recently reported that maternal antibiotic treatment (MAT) of mice in the last days of pregnancy and during lactation dramatically alters the density and composition of the gastrointestinal microbiota of their infants. MAT infants also exhibited enhanced susceptibility to a systemic viral infection and altered adaptive immune cell activation phenotype and function. CD8+ effector T cells from MAT infants consistently demonstrate an inability to sustain interferon gamma (IFN-γ) production in vivo following vaccinia virus infection and in vitro upon T cell receptor (TCR) stimulation. We hypothesize that T cells developing in infant mice with gastrointestinal microbiota dysbiosis and insufficient toll-like receptor (TLR) exposure alters immune responsiveness associated with intrinsic T cell defects in the TCR signaling pathway and compromised T cell effector function. To evaluate this, splenic T cells from day of life 15 MAT infant mice were stimulated in vitro with anti-CD3 and anti-CD28 antibodies prior to examining the expression of ZAP-70, phosphorylated ZAP-70, phospho-Erk-1/2, c-Rel, total protein tyrosine phosphorylation, and IFN-γ production. We determine that MAT infant CD8+ T cells fail to sustain total protein tyrosine phosphorylation and Erk1/2 activation. Lipopolysaccharide treatment in vitro and in vivo, partially restored IFN-γ production in MAT effector CD8+ T cells and reduced mortality typically observed in MAT mice following systemic viral infection. Our results demonstrate a surprising dependence on the gastrointestinal microbiome and TLR ligand stimulation toward shaping optimal CD8+ T cell function during infancy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gastrointestinal Microbiome Dysbiosis in Infant Mice Alters Peripheral CD8+ T Cell Receptor Signaling

González‐Pérez

Lamousé-Smith

2017

Front. Immunol.

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“…In addition to inhibitory surface markers, defective clonal expansion and function of effector CD8 + T cells in neonates is potentially linked to differences in chromatin architecture and histone modification . Neonatal CD8 + T cells have specific epigenetic programming, with adult CD8 + T cells having higher levels of open chromatin marks and less repressive marks, which contribute to differences in gene expression levels between neonates and adults .…”

Section: T‐cell Chromatin Architecturementioning

confidence: 99%

“…In isolated PBMCs from cord blood, neonatal CD8 + T cells produce less perforin than adults. Although both adults and neonates express similar levels of degranulation marker CD107, neonates do not have a detectable amount of granzyme B . Neonatal CD8 + T cells proliferate at a higher rate under homeostatic conditions, but not upon antigenic stimulation, which indicates less efficient clonal expansion.…”

Section: Human Neonatal Cd8+ T Cells Display Innate‐like Featuresmentioning

confidence: 99%

“…Although both adults and neonates express similar levels of degranulation marker CD107, neonates do not have a detectable amount of granzyme B . Neonatal CD8 + T cells proliferate at a higher rate under homeostatic conditions, but not upon antigenic stimulation, which indicates less efficient clonal expansion. Levels of IL‐7 and IL‐7 receptor on neonatal cells are much lower, especially in premature neonates, which contribute to this diminished maturation of T cells and V(D)J recombination .…”

Section: Human Neonatal Cd8+ T Cells Display Innate‐like Featuresmentioning

confidence: 99%

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Dissecting the defects in the neonatal CD8+ T-cell response

Fike

Kumova

Carey

2019

Journal of Leukocyte Biology

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The neonatal period presents a complex scenario where the threshold of reactivity toward colonizing microbiota, maternal antigens, autoantigens, and pathogens must be carefully moderated and balanced. CD8+ T cells are critical for the response against intracellular bacteria and viruses, but this immune compartment maintains altered function relative to adult counterparts because of the unique challenges which infants face. Here, we review our current understanding of the factors which may promote the attenuation and altered function of the neonatal CD8+ T‐cell response and potential avenues for future study. Specifically, we have focused on the neonatal CD8+ T‐cell ontogeny, memory formation, TCR structure and repertoire, TCR inhibitory receptors, and the clinical implications of altered neonatal CD8+ T‐cell function. Special emphasis has been placed on examining the response of preterm neonates relative to term neonates and adults.

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Protein complexes associated with β‐catenin differentially influence the differentiation profile of neonatal and adult CD8⁺ T cells

Hernández-Acevedo

López-Portales

Gutiérrez-Reyna

et al. 2019

Journal Cellular Physiology

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The canonical Wnt signaling pathway is a master cell regulator involved in CD8+ T cell proliferation and differentiation. In human CD8+ T cells, this pathway induces differentiation into memory cells or a “stem cell memory like” population, which is preferentially present in cord blood. To better understand the role of canonical Wnt signals in neonatal or adult blood, we compared the proteins associated with β‐catenin, in nonstimulated and Wnt3a‐stimulated human neonatal and adult naive CD8+ T cells. Differentially recruited proteins established different complexes in adult and neonatal cells. In the former, β‐catenin‐associated proteins were linked to cell signaling and immunological functions, whereas those of neonates were linked to proliferation and metabolism. Wnt3a stimulation led to the recruitment and overexpression of Wnt11 in adult cells and Wnt5a in neonatal cells, suggesting a differential connexion with planar polarity and Wnt/Ca2+ noncanonical pathways, respectively. The chromatin immunoprecipitation polymerase chain reaction β‐catenin was recruited to a higher level on the promoters of cell renewal genes in neonatal cells and of differentiation genes in those of adults. We found a preferential association of β‐catenin with CBP in neonatal cells and with p300 in the adult samples, which could be involved in a higher self‐renewal capacity of the neonatal cells and memory commitment in those of adults. Altogether, our results show that different proteins associated with β‐catenin during Wnt3a activation mediate a differential response of neonatal and adult human CD8+ T cells.

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CD8 + T Cells from Human Neonates Are Biased toward an Innate Immune Response

Cited by 59 publications

References 43 publications

Gastrointestinal Microbiome Dysbiosis in Infant Mice Alters Peripheral CD8+ T Cell Receptor Signaling

Gastrointestinal Microbiome Dysbiosis in Infant Mice Alters Peripheral CD8+ T Cell Receptor Signaling

Dissecting the defects in the neonatal CD8+ T-cell response

Protein complexes associated with β‐catenin differentially influence the differentiation profile of neonatal and adult CD8⁺ T cells

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CD8 + T Cells from Human Neonates Are Biased toward an Innate Immune Response

Cited by 59 publications

References 43 publications

Gastrointestinal Microbiome Dysbiosis in Infant Mice Alters Peripheral CD8+ T Cell Receptor Signaling

Gastrointestinal Microbiome Dysbiosis in Infant Mice Alters Peripheral CD8+ T Cell Receptor Signaling

Dissecting the defects in the neonatal CD8+ T-cell response

Protein complexes associated with β‐catenin differentially influence the differentiation profile of neonatal and adult CD8+ T cells

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Protein complexes associated with β‐catenin differentially influence the differentiation profile of neonatal and adult CD8⁺ T cells