PLoS ONE (Jan 2017)

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

  • Haruyo Nakajima-Adachi,
  • Kyoko Shibahara,
  • Yoko Fujimura,
  • Jun Takeyama,
  • Erika Hiraide,
  • Akira Kikuchi,
  • Hitoshi Murakami,
  • Akira Hosono,
  • Tomonori Nochi,
  • Yoshio Wakatsuki,
  • Naoki Shimojo,
  • Shuichi Kaminogawa,
  • Ryuichiro Sato,
  • Hiroshi Kiyono,
  • Satoshi Hachimura

DOI
https://doi.org/10.1371/journal.pone.0172795
Journal volume & issue
Vol. 12, no. 2
p. e0172795

Abstract

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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.