Early life exposures shape the CD4+ T cell transcriptome, influencing proliferation, differentiation, and mitochondrial dynamics later in life

Catherine G Burke,Christina M Post,B Paige Lawrence,Jason R Myers,Lisbeth A Boule,Paul S Brookes

doi:10.1038/s41598-019-47866-2

Catherine G Burke, Christina M Post + Show 4 more

Open Access

https://doi.org/10.1038/s41598-019-47866-2

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Journal: Scientific Reports	Publication Date: Aug 7, 2019
Citations: 6	License type: open-access

Affiliation: University of Rochester

Abstract

Early life environmental exposures drive lasting changes to the function of the immune system and can contribute to disease later in life. One of the ways environmental factors act is through cellular receptors. The aryl hydrocarbon receptor (AHR) is expressed by immune cells and binds numerous xenobiotics. Early life exposure to chemicals that bind the AHR impairs CD4+ T cell responses to influenza A virus (IAV) infection in adulthood. However, the cellular mechanisms that underlie these durable changes remain poorly defined. Transcriptomic profiling of sorted CD4+ T cells identified changes in genes involved in proliferation, differentiation, and metabolic pathways were associated with triggering AHR during development. Functional bioassays confirmed that CD4+ T cells from infected developmentally exposed offspring exhibit reduced proliferation, differentiation, and cellular metabolism. Thus, developmental AHR activation shapes T cell responsive capacity later in life by affecting integrated cellular pathways, which collectively alter responses later in life. Given that coordinated shifts in T cell metabolism are essential for T cell responses to numerous challenges, and that humans are constantly exposed to many different types of AHR ligands, this has far-reaching implications for how AHR signaling, particularly during development, durably influences T cell mediated immune responses across the lifespan.

Highlights

Every day humans are exposed to myriad environmental factors through the air we breathe, the food and beverages we consume, products we interact with, and many activities or jobs we undertake
Adult offspring that were developmentally exposed to the aryl hydrocarbon receptor (AHR) ligand TCDD have fewer Th1, T follicular helper (Tfh), and Th17 cells upon infection with influenza A virus (IAV) (Fig. 1a–c)
To identify which cellular pathways were changed as a consequence of triggering AHR during development, we compared the transcriptome of CD4+ T cells from IAV infected adult mice that were or were not exposed to TCDD during development

Summary

Introduction

Every day humans are exposed to myriad environmental factors through the air we breathe, the food and beverages we consume, products we interact with, and many activities or jobs we undertake. After IAV infection, we separated resting and responding CD4+ T cells and performed unbiased transcriptome profiling to identify differentially expressed genes in adult offspring that were and were not exposed to TCDD during development. Adult offspring that were developmentally exposed to the AHR ligand TCDD have fewer Th1, Tfh, and Th17 cells upon infection with IAV (Fig. 1a–c).

Results

Conclusion