Frequency and affinity of dietary antigens gradually inactivate CD4+ T cells during oral tolerance 9384

Abstract Description CD4 T cells specific to dietary antigens inactivate through different mechanisms that include deletion, anergy, and acquisition of regulatory capacities. The factors that influence these different outcomes are not known. The aim of this work was to analyze the role of antigen-associated factors (e.g., concentration, frequency, TCR affinity) in determining CD4 T cell fates during oral tolerance induction. We adoptively transferred naïve CD45.1 FoxP3GFP OT-II CD4 T cells and fed the mice with different regimes of the model antigen ovalbumin (OVA) recognized by OT-II cells. A single dose of OVA fed to the mice induced OT-II proliferation accompanied by upregulation of FoxP3, peaking at 48 hours after OVA administration. At later time points, FoxP3+ cells decreased and anergic cells gradually became the dominant population. Repetitive administration of OVA induced the expression of anergy-associated molecules (e.g., Lag-3, Nrp-1) and transcription factors (e.g., TOX, Helios) in a dose-dependent manner suggesting that continuous exposure to cognate antigen induces a more profound CD4 T cell inactivation. In vitro examination of tolerogenic fates using different affinity ligands showed that weak TCR activation is associated with the development of anergy. Collectively, these results denote peripheral tolerance to oral antigens is a dynamic process, where CD4 T cells acquire FoxP3 expression in a short-lived manner, progress into an anergic phenotype and are ultimately deleted. Funding Sources FUNDING: CONAHCYT (FORDECYT-303046). Topic Categories Mucosal and Regional Immunology (MUC)