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

Abstract

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.

The potential of the microbiota to influence vaccine responses

“…A recent study reported that maternal antibiotic treatment in mice led to significantly reduced Ag‐specific IFN‐γ production by CD8 + T cells in the mice born to these mothers after vaccinia virus infection . This effect was partially rescued by the oral administration of LPS, which suggests that the microbiota can indeed influence Ag‐specific T cell responses, although whether these effects were long‐lasting was not assessed. Similarly, the recall production of IFN‐γ or IL‐5 from Ag‐stimulated splenocytes isolated from mice immunized with HSA, and CT was completely ablated in antibiotic‐treated mice .…”

Changes in Gut Microbiota Prior to Influenza A Virus Infection Do Not Affect Immune Responses in Pups or Juvenile Mice

“…Studies investigating the impact of ABX-induced changes on GM composition and susceptibility to influenza A virus (IAV) infection in mice have focused on the impact of ABX treatment during infection of adult animals, which resulted in exacerbated disease (Ichinohe et al, 2011 ; Abt et al, 2012 ; Gonzalez-Perez et al, 2016 ; Gonzalez-Perez and Lamousé-Smith, 2017 ). Our studies have therefore focused on investigating how ABX treatment prior to, but not during, IAV infection impacts the GM composition, as well as the development of disease and immunity following subsequent IAV infection.…”

Influence of maternal microbiota during pregnancy on infant immunity

“…Tormo-Badia et al [20] observed significantly increased proportions of CD8 + T cells in the mesenteric lymph nodes (MLN) of pups born to non-obese diabetic (NOD) dams treated with antibiotics during pregnancy compared to control pups. Follow-up experiments revealed that the observed CD8 + T cell impairment was driven by an altered activation and expression of T cell receptor (TCR) critical for sustained cytokine production [22]. Follow-up experiments revealed that the observed CD8 + T cell impairment was driven by an altered activation and expression of T cell receptor (TCR) critical for sustained cytokine production [22].…”

“…Similarly, pups born to mothers treated with antibiotics orally during gestation and postpartum exhibited increased susceptibility to vaccinia virus infection and reduced interferon (IFN)-γ production by CD8 + T cells when compared to controls [21]. Follow-up experiments revealed that the observed CD8 + T cell impairment was driven by an altered activation and expression of T cell receptor (TCR) critical for sustained cytokine production [22]. We recently showed, using mouse models, that altering maternal intestinal microbiota during pregnancy alone impacted inherent immunity in pups at 14 days postpartum [1] (Fig.…”