Environmental cues received during development shape dendritic cell responses later in life

Area of Science:

• Immunology
• Developmental Biology
• Environmental Health

Background:

• Environmental signals, particularly via the aryl hydrocarbon receptor (AHR), are crucial for immune system development and function.
• Developmental exposure to AHR-binding chemicals can lead to lasting immune dysregulation, affecting T cell responses to infections like influenza A virus (IAV).
• While AHR ligands affect adult dendritic cells (DCs), the long-term impact of developmental AHR activation on DCs remains largely unknown.

Purpose of the Study:

• To investigate the long-term consequences of early-life aryl hydrocarbon receptor (AHR) activation on dendritic cell (DC) function and migration.
• To determine how developmental AHR signaling influences the ability of DCs to activate T cells later in life.
• To identify molecular pathways affected by developmental AHR activation that contribute to altered DC function.

Main Methods:

• Utilized developmental exposure models in mice to activate the aryl hydrocarbon receptor (AHR).
• Assessed dendritic cell (DC) function, including T cell activation (CD4+ and CD8+), in vitro and in vivo.
• Evaluated DC migration using in vivo and ex vivo assays and conditional knockout mice lacking AHR in CD11c+ cells.
• Performed gene expression analysis to identify affected molecular pathways.

Main Results:

• Developmental AHR activation durably impaired the ability of DCs to activate naive IAV-specific CD8+ T cells, but not CD4+ T cells.
• DCs from developmentally exposed offspring exhibited reduced migration capacity in both in vivo and ex vivo assessments.
• Conditional knockout studies indicated that impaired DC emigration is intrinsic to DCs, independent of other cell types.
• Gene expression profiling revealed altered expression of genes involved in DC migration, antigen processing, and presentation, including Lrp1, Itgam, and Fcgr1.

Conclusions:

• Early-life activation of the aryl hydrocarbon receptor (AHR) induces persistent, detrimental changes in dendritic cell (DC) function and migration.
• These findings highlight critical developmental windows where environmental exposures can permanently shape immune responses.
• The study provides novel insights into the mechanisms by which early environmental cues mediated by AHR signaling influence long-term immune health.