Gastrointestinal Microbiome Dysbiosis in Infant Mice Alters Peripheral CD8+T Cell Receptor Signaling.
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) productionin vivofollowing vaccinia virus infection andin vitroupon 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 stimulatedin vitrowith 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 treatmentin vitroandin 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.
Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University Medical Center , New York, NY , USA.
Gabriela
G
Gonzalez-Perez
Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University Medical Center , New York, NY , USA.
Esi S N
ES
Lamousé-Smith
CD8+ T cells; Erk2; T cell signaling; antibiotics; dysbiosis; immunity; microbiome; neonatal