Dynamic fates of dietary antigen-specific T helper cells in a model of early life oral tolerance

Dietary antigens are first encountered in the gut during early life, when the immune system and microbiota are still maturing. In healthy individuals, oral tolerance develops towards dietary antigens: an active process which results in local and systemic immune unresponsiveness to antigens first encountered in the gut. Despite a wealth of research describing mechanisms contributing to oral tolerance in adult rodent models, questions remain about how the early life environment impacts oral tolerance development. We set out to characterize the fate(s) of CD4+ T cells during oral tolerance development using a robust early life mouse model, where controlled oral doses of dietary antigen are given directly to pups during the pre-weaning period. Orally administering 2mg of ovalbumin (OVA) daily during the third week of life was sufficient to confer oral tolerance to OVA in female and male C57BL/6 and BALB/c mice. Following early life oral OVA exposure, a large proportion of OVA-specific CD4+ T cells acquired a Th2 phenotype, alongside some OVA-specific Tregs. Following systemic challenges of OVA with an adjuvant, both OVA-specific Tregs and Th lineage-negative cells expressing anergy markers were detectable in pups given early life oral OVA, while OVA-specific Th2 cells were suppressed in comparison to pups who never received early life oral OVA. These data highlight the diverse fates of CD4+ T cells during early life oral tolerance development and maintenance, and we present a model to study oral tolerance during the early life period when dietary antigens are first encountered.