Weaning off food allergy

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Regulatory T (T_Reg) cells are induced in the small intestine by exposure to solid food during weaning and protect against otherwise strong immune responses to ingested antigens, according to new research in Science. The results suggest that exposing children to a variety of food types from an early age might be an important factor in preventing the development of severe food allergies.

Antigen-free mice are derived by breeding germ-free mice fed an elemental liquid diet (filtered to deplete macromolecules), such that the offspring have never been exposed to microbial or food antigens. Surh and colleagues show that these antigen-free mice have smaller lymphocyte numbers in the small intestinal lamina propria (siLP), but not in the colonic lamina propria (cLP), compared with specific pathogen-free (SPF) mice, which could be accounted for by the depletion of memory CD4⁺ T cells in the siLP. These results suggest that CD4⁺ T cells are activated by food antigens in the small intestine but by the microbiota in the colon.

CD4⁺ T_Reg cells are abundant in the intestine and are known to be involved in oral tolerance. The total number of siLP T_Reg cells was five-fold lower in antigen-free mice than in germ-free or SPF mice; by contrast, antigen-free mice had a similar number of cLP T_Reg cells to germ-free mice, which was two-fold lower than in SPF mice. In SPF mice, 50–70% of the T_Reg cells in siLP and cLP are peripherally derived (pT_Reg cells; identified by low levels of expression of neuropilin 1); these pT_Reg cells are rare in the cLP of germ-free mice but present in the siLP, whereas they are depleted from both siLP and cLP of antigen-free mice. Therefore, dietary antigens induce most of the pT_Reg cells in the siLP.

The number of pT_Reg cells in the siLP was low in all mice before weaning but increased shortly after weaning onto a normal chow diet. Weaning neonatal germ-free mice onto an antigen-free diet prevented the development of siLP pT_Reg cells. Furthermore, when adult germ-free mice were switched to an antigen-free diet, the number of pT_Reg cells in siLP was decreased by 40%. Thus, siLP pT_Reg cells develop and are maintained in response to dietary antigens.

Antigen-free mice mounted a greater T cell response in the gut-associated lymphoid tissues than germ-free or SPF mice after adoptive transfer of ovalbumin (OVA)-specific T cells followed by oral OVA. Furthermore, the expanded OVA-specific T cell population in antigen-free mice expressed lower levels of forkhead box P3 (FOXP3) than in germ-free or SPF mice and had a greater tendency to differentiate to a T helper 1 (T_H1) cell phenotype. The results show that siLP pT_Reg cells are required to prevent a default pro-inflammatory T cell response to new dietary antigens. In support of this, neonatal SPF mice weaned onto an amino acid diet (to prevent the development of siLP pT_Reg cells) had increased susceptibility to OVA-induced intestinal allergy than control mice weaned onto a chow diet.

food- and microbe-induced T_Reg cell populations work together to prevent food allergies

In summary, weaning onto solid food induces siLP pT_Reg cells, which are required to suppress the immune response to dietary antigens. Given the already established role of the microbiota in promoting oral tolerance, the authors suggest that food- and microbe-induced T_Reg cell populations work together to prevent food allergies throughout the digestive tract.