Abstract
Environmental signals mediated via the aryl hydrocarbon receptor (AHR) shape the developing immune system and influence immune function. Developmental exposure to AHR binding chemicals causes persistent changes in CD4+ and CD8+ T cell responses later in life, including dampened clonal expansion and differentiation during influenza A virus (IAV) infection. Naïve T cells require activation by dendritic cells (DCs), and AHR ligands modulate the function of DCs from adult organisms. Yet, the consequences of developmental AHR activation by exogenous ligands on DCs later in life has not been examined. We report here that early life activation of AHR durably reduces the ability of DC to activate naïve IAV-specific CD8+ T cells; however, activation of naïve CD4+ T cells was not impaired. Also, DCs from developmentally exposed offspring migrated more poorly than DCs from control dams in both in vivo and ex vivo assessments of DC migration. Conditional knockout mice, which lack Ahr in CD11c lineage cells, suggest that dampened DC emigration is intrinsic to DCs. Yet, levels of chemokine receptor 7 (CCR7), a key regulator of DC trafficking, were generally unaffected. Gene expression analyses reveal changes in Lrp1, Itgam, and Fcgr1 expression, and point to alterations in genes that regulate DC migration and antigen processing and presentation as being among pathways disrupted by inappropriate AHR signaling during development. These studies establish that AHR activation during development causes long-lasting changes to DCs, and provide new information regarding how early life environmental cues shape immune function later in life.
Highlights
The immune system develops during gestation and following birth
We used an equivalent number of dendritic cell (DC) from adult infected offspring of vehicle or TCDD exposed dams to activate naïve, carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled T cell receptor (TCR) transgenic T cells ex vivo
CD8+ T cells cultured with DCs from offspring of TCDD-treated dams secreted roughly half as much interferon gamma (IFNγ) as CD8+ T cells stimulated by DCs from vehicle controls (Fig 1D)
Summary
The immune system develops during gestation and following birth. The environment experienced in utero and during early postnatal life can influence the immune system, leading to durable changes that influence health later in life. Research in animal models further supports the idea that immune function at maturity is influenced by early life exposures [5,6,7,8,9], and that the developing immune system is more sensitive than the mature immune system to enduring modulation by environmental factors [10,11,12] While these studies reveal links between developmental exposures and life-long changes in immune function, how early life exposures shape the immune system is not fully understood. Several different human cohort studies show strong associations between early life exposure to these AHR-binding pollutants and altered immune function, including more severe or frequent respiratory infections and decreased antibody responses to vaccinations [23,24,25,26,27,28]. Given the pivotal role that DCs play in establishing and maintaining T cell responses, the ability of early life AHR activation to affect DC functional properties later in life has many implications as we seek to understand AHR-mediated regulation of the immune system, and to understand how the early life environmental cues shape the way the immune system is poised to respond
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
