Induction of anergy in Th1 lymphocytes by oral tolerance. Importance of antigen dosage and frequency of feeding.

Oral tolerance, a biologically relevant pathway for inducing peripheral tolerance in T lymphocytes, occurs by two distinct mechanisms. Multiple low doses of antigen induce regulatory T lymphocytes that secrete immunosuppressive cytokines, whereas feeding a single high dose of antigen induces anergy of antigen-specific Th1 lymphocytes (diminished IgG2a, IL-2, and IFNgamma) with intact Th2 responses (IgG1 and IL-4). Anergy was demonstrated by the ability to reverse tolerant state after culturing tolerant cells in rIL-2. Reversal of the tolerant state was established in vitro by increase in frequency of IL-2 secreting cells, and in vivo by specific IgG2a production in irradiated mice adoptively transferred with cells cultured in rIL-2. Inasmuch as the induction of anergy was inhibited by the presence of antibodies specific for the tolerizing antigen, it appears that the oral induction of anergy might depend on the systemic dissemination of antigen (or its fragments) absorbed from the gut. It is suggested that tolerance is insured by the fact that this absorbed antigen is presented to Th1 lymphocytes in draining lymph nodes in the absence of inflammatory and costimulatory molecules.