Some people are allergic to specific foods (e.g., peanuts, milk, eggs, etc.) that can trigger immune responses of varying intensity if they are accidentally consumed. In most cases, the foods we consume subtly avoid the immune response of the digestive system through a mechanism called “oral tolerance,” although this mechanism is not well understood. Previous studies suggest that regulatory T cells (especially peripheral regulatory T cells, pTreg) may be involved in this process. pTreg cells are differentiated from conventional T cells and are mainly located in the intestine. This distribution feature implies that they are likely influenced by intestinal commensal bacteria. Previous experiments found that a fraction of antigen-specific CD4+ T cells were able to transform into pTreg cells by administering antigens orally to mice, but whether this was related to specific food types was not clear. To explain this, Charles D. Surh’s group from the Institute of Immunology at the Korea Institute of Basic Medical Sciences conducted a detailed study, and the relevant results were published in a recent issue of the journal Science. First, they performed a very impressive experiment: a series of AF (Antigen Free) mice was obtained by chemically controlling the feeding of GF mice to a diet identified as not containing any macromolecular compounds (i.e., effectively avoiding the presence of food antigens). The number of lymphocytes in the subcutaneous lamina propria of the small intestine was significantly lower in the AF mice, with the most pronounced number of CD4+ T cells. This phenomenon suggests that the number of CD4+ T cells in the intestine is regulated by antigens in the food. Later, the authors found that the number of CD4+ Treg cells in the lamina propria of the small intestine was also significantly lower in AF mice than in SPF mice, a phenotype similar to that of GF. By further analysis, a large component of this reduced Treg cell fraction was pTreg cells. In conclusion, the above results suggest that antigens in food can promote the proliferation and differentiation of pTreg cells in the lamina propria of the intestine. Next, the authors analyzed exactly which food antigens (liquid or solid) are relevant for the development of intestinal pTreg. Similar to the above, they fed chewable food to different types of mice (SPF, AF, GF). The results showed that the number of pTreg cells in the lamina propria of the small intestine was significantly increased in the experimental group of mice compared to the control group. This suggests that the antigens in solid foods have an important role in the development of such cells in the intestine. In addition to food antigens, intestinal microorganisms also play an important role in the development of pTreg. Previous studies have shown that gut microbes can promote the differentiation of RORgamma t+ Treg cells. The results showed that the number of such cells was significantly reduced in the intestine of both AF mice and GF mice (positive control). In addition, the establishment of RORgamma t- Treg cells was also significantly lower in AF mice, which was different from that in GF mice. The authors found that the number of RORgamma t+ Treg cells was influenced by gut microorganisms and the number of ROR gamma- Treg cells was influenced by food antigens, either by bacterial colonization or by changing the feeding method. Later, the authors found that the number of intestinal CD103+ CD11b+ DCs was also significantly decreased in AF mice. This fraction of cells was mainly used to induce differentiation of Treg cells; in contrast, the number of CD103- CD11b+ DC in the intestine of AF mice was as much as three times higher than that of SPF(GF) mice. In conclusion, the authors demonstrated through the above experiments that antigens in food are key factors in the induction of pTreg cell differentiation in the lamina propria of the small intestine, and that the latter would play a very critical role in maintaining the intestinal immune tolerance environment; the lack of antigens in food would lead to a decrease in the number of DCs inducing pTreg production in the intestine, which in turn would affect the number of pTreg. Since this fraction of antigens is often present in solid foods, it also reveals why small children often develop food allergy symptoms that slowly disappear over time.