Oral tolerance in the absence of naturally occurring Tregs
Daniel Mucida, Nino Kutchukhidze, Agustin Erazo, Momtchilo Russo, Juan J. Lafaille, Maria A. Curotto de Lafaille
Daniel Mucida, Nino Kutchukhidze, Agustin Erazo, Momtchilo Russo, Juan J. Lafaille, Maria A. Curotto de Lafaille
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Research Article Immunology

Oral tolerance in the absence of naturally occurring Tregs

Abstract

Mucosal tolerance prevents pathological reactions against environmental and food antigens, and its failure results in exacerbated inflammation typical of allergies and asthma. One of the proposed mechanisms of oral tolerance is the induction of Tregs. Using a mouse model of hyper-IgE and asthma, we found that oral tolerance could be effectively induced in the absence of naturally occurring thymus-derived Tregs. Oral antigen administration prior to i.p. immunization prevented effector/memory Th2 cell development, germinal center formation, class switching to IgE, and lung inflammation. Oral exposure to antigen induced development of antigen-specific CD4+CD25+Foxp3+CD45RBlow cells that were anergic and displayed suppressive activity in vivo and in vitro. Oral tolerance to the Th2 allergic response was in large part dependent on TGF-β and independent of IL-10. Interestingly, Tregs were also induced by single i.p. immunization with antigen and adjuvant. However, unlike oral administration of antigen, which induced Tregs but not effector T cells, i.p. immunization led to the simultaneous induction of Tregs and effector Th2 cells displaying the same antigen specificity.

Authors

Daniel Mucida, Nino Kutchukhidze, Agustin Erazo, Momtchilo Russo, Juan J. Lafaille, Maria A. Curotto de Lafaille

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Effect of previous OVA-feeding on Treg and effector/memory T cell develo...
Effect of previous OVA-feeding on Treg and effector/memory T cell development. The expression of CD25 and CD45RB by OVA-specific T cells from the Tol (OVA fed + OVA-HA immunized), Imm (OVA-HA immunized), and Oral (OVA-fed) groups (as defined in Figure 1A) were analyzed after immunization. mLN cells were stained with antibodies to CD25, CD45RB, and CD4 and analyzed by FACS. (A) Representative dot plots of gated CD4+ cells from the Tol and Imm groups at day 22. Similar staining and quadrant gating was used to determine the percentage of CD25–CD45RBlow (effector/memory T cells) and CD25+CD45RBlow (Treg phenotype) cells in the experimental groups at various times after immunization (see B). (B) Kinetics of appearance of CD25–CD45RBlow (effector/memory T cells) and CD25+CD45RBlow (Treg) cells. On day 0, before immunization, and days 4 and 10 after immunization, mLN cells from Tol (squares), Imm (diamonds), and Oral (triangles) groups were analyzed for the presence of CD4 cells with effector/memory T cell or Treg phenotypes as described above. Results are expressed as mean ± SD of 5–15 mice per group per time point. (C) Increased percentage of CD25+CD45RBlow in BAL CD4 cells from Tol mice. BAL was collected from mice of the Tol and Imm groups on day 22. BAL cells were stained with antibodies to CD4, CD25, and CD45RB. The plots show gated CD4+ cells from representative samples. The numbers in the upper right of the plots indicate quadrant percentages. CD25+/CD25– indicates the ratio between CD25+CD45RBlow and CD25–CD45RBlow cells in each sample.