Tetramer-based examination of peanut specific CD4 T cells reveals that oral tolerance is mediated by CNS1-independent generation of Foxp3+ regulatory T cells

Abstract

Food allergy is an adverse immune response against food antigens. Under steady-state conditions, the immune system is capable of generating oral tolerance that prevents allergic responses to orally-administrated innocuous antigens. However, studies on oral tolerance and food allergy have been limited due to lack of methods detecting food allergen-specific CD4+ T cells. Here, we identified an I-Ab epitope in a peanut allergen Ara h 1 and produced Arah1-I-Ab tetramer. Tetramer-based research revealed that peanut ingestion in advance of oral immunization could restrict the size of Arah1-specific T cells, but promote the generation of Arah1-specific Foxp3+ regulatory CD4 T (Treg) cells, reflecting the establishment of oral tolerance. Furthermore, oral tolerance was established in CNS1 KO mice with a defect in the capacity of de novo generation of Treg cells. Oral tolerance in CNS1 KO mice was mainly achieved by the increased generation of Arah1-specific Treg cells, instead of suppressing proliferation of Arah1-specific CD4 T cells. Our data indicate that oral tolerance to food antigens is mediated through complicated mechanisms that cannot be solely explained by the CNS1-dependent induction of food antigen-specific Treg cells.