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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CD4+CD25+ T cells induced by oral tolerance are anergic and suppressive ...
CD4+CD25+ T cells induced by oral tolerance are anergic and suppressive in vitro. T/B monoclonal mice were administered OVA in drinking water and immunized with OVA-HA as represented in Figure 1A. Ten days after immunization, spleen and mLN cells were collected and pooled for the sorting of CD4+CD25+ and CD4+CD25– populations. Purified CD4+CD25– and CD4+CD25+ cells from Tol T/B monoclonal mice (Tol) or from BALB/c mice were stimulated in vitro with anti-CD3 antibodies and APCs (2 × 104 CD4 cells + 4 × 104 APC cells/well). For coculture experiments, 2 × 104 CD4+CD25– BALB/c cells (responder cells) were stimulated with anti-CD3 antibodies and APCs in the presence of putative suppressor cells from Tol or BALB/c mice at responder/suppressor ratios of 1.0:1.0, 1.0:0.3, and 1.0:0.1. Proliferation was determined by 3H-thymidine (3H-TdR) incorporation. Results are expressed as mean ± SD of triplicate wells.