Dietary Antigens Limit Mucosal Immunity by Inducing Regulatory T Cells in the Small Intestine

Kwang Soon Kim, Sung-Wook Hong, Daehee Han, Jaeu Yi, Jisun Jung, Bo-Gie Yang, Jun Young Lee, Minji Lee, Charles D. Surh

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In a clockwise direction from left; J. Jung, S.W. Hong, K.S. Kim, J. Yi, J.Y. Lee, M. Lee, D. Han, C.D. Surh, B.G. Yang

The gastrointestinal organs are chronically exposed to massive amount of diverse enteric antigens (Ags), most derived from diet and intestinal microbes both of which are benign and beneficial to our body. Immunological tolerance to these enteric Ags is critical for ensuring immune homeostasis and for preventing overt immune reactions such as food allergy and colitis.

In general, dietary Ags are rendered nonimmunogenic via oral tolerance mechanisms that involve immunosuppressive regulatory T (Treg) cells expressing Foxp3, especially peripheral Treg (pTreg) cells that develop extrathymically from conventional CD4+ T cells. pTreg cells are abundant in the intestine and colonic pTreg cells develop in response to intestinal microbes as most colonic pTreg cells are depleted in germ-free (GF) mice. However, GF mice possess normal numbers of pTreg cells in the small intestine, the origin of which yet to be elucidated.

In our latest research reported in Science, we examined whether pTreg cells are generated in response to a typical diet. To address this issue, we studied the effect of depleting dietary Ags by raising mice on a chemically defined elemental diet devoid of macromolecules.

Comparative analyses of such Ag-free (AF) mice with conventional specific pathogen-free (SPF) and GF mice showed that the majority of the small intestinal pTreg cells are induced by dietary Ags from solid foods, have limited life span and distinguishable from intestinal microbiota-induced pTreg cells that express the transcription factor, RORgt.

Oral administration of a norminal Ag under experimental conditions can induce a fraction of Ag-specific CD4+ T cells to differentiate pTreg cells efficiently in the small intestine. However, in AF mice, mucosal immune responses to newly introduced Ag are more prodigious but the differentiation of Ag-specific pTreg cells is less efficient in the small intestine relative to those in SPF and GF mice.

These results suggested that small intestinal pTreg cells are essential to creating tolerogenic intestinal environment and suppressing a default strong immune response to dietary Ags and could also explain why childhood allergies spontaneously dissipate with time.

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