Critical role of intestinal interleukin-4 modulating regulatory T cells for desensitization, tolerance, and inflammation of food allergy

• Published in: PloS one Vol. 12; no. 2; p. e0172795
• Main Authors: Nakajima-Adachi, Haruyo, Shibahara, Kyoko, Fujimura, Yoko, Takeyama, Jun, Hiraide, Erika, Kikuchi, Akira, Murakami, Hitoshi, Hosono, Akira, Nochi, Tomonori, Wakatsuki, Yoshio, Shimojo, Naoki, Kaminogawa, Shuichi, Sato, Ryuichiro, Kiyono, Hiroshi, Hachimura, Satoshi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.02.2017; Public Library of Science (PLoS)
• Subjects: Albumen; Allergens; Allergens - adverse effects; Allergens - immunology; Analysis; Animal models; Animal tissues; Animals; Antigens; Biology and Life Sciences; Biotechnology; Body weight loss; CD4 antigen; Cytokines; Dendritic cells; Desensitization; Desensitization (Psychology); Desensitization, Immunologic; Diet; Drug dosages; Female; Food; Food allergies; Food hypersensitivity; Food Hypersensitivity - genetics; Food Hypersensitivity - immunology; Food safety; Foxp3 protein; Immune Tolerance - genetics; Immunological tolerance; Immunology; Immunoregulation; Immunotherapy; Inflammation; Interleukin; Interleukin 4; Interleukin-4 - biosynthesis; Interleukin-4 - immunology; Intestine; Intestines - metabolism; Intravenous administration; Life sciences; Lymph nodes; Lymph Nodes - immunology; Lymphocytes; Lymphocytes T; Medicine and Health Sciences; Mice; Oral administration; Ovalbumin; Ovalbumin - biosynthesis; R&D; Receptors; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Recombination; Research & development; Research and Analysis Methods; Restarting; Rodents; Spleen; T cell receptors; T cells; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Weight loss; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0172795

The mechanism inducing either inflammation or tolerance to orally administered food allergens remains unclear. To investigate this we analyzed mouse models of food allergy (OVA23-3) and tolerance (DO11.10 [D10]), both of which express ovalbumin (OVA)-specific T-cell receptors. OVA23-3, recombination activating gene (RAG)-2-deficient OVA23-3 (R23-3), D10, and RAG-2-deficient D10 (RD10) mice consumed a diet containing egg white (EW diet) for 2-28 days. Interleukin (IL)-4 production by CD4+ T cells was measured as a causative factor of enteropathy, and anti-IL-4 antibody was used to reveal the role of Foxp3+ OVA-specific Tregs (aiTreg) in this process. Unlike OVA23-3 and R23-3 mice, D10 and RD10 mice did not develop enteropathy and weight loss on the EW diet. On days 7-10, in EW-fed D10 and RD10 mice, splenic CD4+ T cells produced significantly more IL-4 than did those in the mesenteric lymph nodes (MLNs); this is in contrast to the excessive IL-4 response in the MLNs of EW-fed OVA23-3 and R23-3 mice. EW-fed R23-3 mice had few aiTregs, whereas EW-fed RD10 mice had them in both tissues. Intravenous injections of anti-IL-4 antibody recovered the percentage of aiTregs in the MLNs of R23-3 mice. On day 28, in EW-fed OVA23-3 and R23-3 mice, expression of Foxp3 on CD4+ T cells corresponded with recovery from inflammation, but recurrence of weight loss was observed on restarting the EW diet after receiving the control-diet for 1 month. No recurrence developed in D10 mice. Excessive IL-4 levels in the MLNs directly inhibited the induction of aiTregs and caused enteropathy. The aiTregs generated in the attenuation of T cell-dependent food allergic enteropathy may function differently than aiTregs induced in a tolerance model. Comparing the two models enables to investigate their aiTreg functions and to clarify differences between inflammation with subsequent desensitization versus tolerance.