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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Neutralization of TGF-β in vivo inhibits early Foxp3 expression. T/B mon...
Neutralization of TGF-β in vivo inhibits early Foxp3 expression. T/B monoclonal mice were injected with anti–TGF-β 1 day before and 3 days after the beginning of administration of 1% OVA in the drinking water. After 5 days of oral-OVA, CD4+ mLN cells were analyzed for expression of CD45RB and CD25 by FACS and for expression of Foxp3 by real-time PCR. (A) mLN cells from mice that received oral-OVA alone, from mice that received anti–TGF-β antibodies and oral-OVA, and from untreated T/B monoclonal mice were stained with antibodies for CD4, CD45RB, and CD25. The figure shows representative plots of CD4+ gated cells. (B) CD4+ cells from pooled mLN (4 mice per group) were sorted in a MoFlo flow cytometer into CD45RBlowCD4+CD25+, CD45RBlowCD4+CD25–, CD45RBhiCD4+CD25+, and CD45RBhiCD4+CD25– fractions. Foxp3 expression in the samples was determined by real-time PCR. Results are expressed as mean ± SD of triplicate wells.