Lactobacillus reuteri–induced Regulatory T cells Protect against an Allergic Airway Response in Mice

RATIONALE: We have previously demonstrated that oral treatment with live Lactobacillus reuteri can attenuate major characteristics of the asthmatic response in a mouse model of allergic airway inflammation. However, the mechanisms underlying these effects remain to be determined. OBJECTIVES: We tested the hypothesis that regulatory T cells play a major role in mediating L. reuteri-induced attenuation of the allergic airway response. METHODS: BALB/c mice were treated daily with L. reuteri by gavage. Flourescent-activated cell sorter analysis was used to determine CD4(+)CD25(+)Foxp3(+)T cell populations in spleens following treatment with L. reuteri or vehicle control. Cell proliferation assays were performed on immunomagnetic bead separated CD4(+)CD25(+) and CD4(+)CD25(-) T cells. CD4(+)CD25(+) T cells isolated from, ovalbumin naive, L. reuteri treated mice were transferred into ovalbumin-sensitized mice. Following antigen challenge the airway responsiveness, inflammatory cell influx and cytokine levels in bronchoalveolar lavage fluid of recipient mice were assessed. MEASUREMENTS AND MAIN RESULTS: Following 9 days of oral L. reuteri treatment, the percentage and total number of CD4(+)CD25(+)Foxp3(+)T cells in spleens significantly increased. CD4(+)CD25(+) cells isolated from L. reuteri-fed animals also had greater capacity to suppress T-effector cell proliferation. Adoptive transfer of CD4(+)CD25(+) T cells from L. reuteri-treated mice to ovalbumin-sensitized animals attenuated airway hyper-responsiveness and inflammation in response to subsequent antigen challenge. CONCLUSIONS: These results strongly support a role for nonantigen-specific CD4(+)CD25(+)Foxp3(+) regulatory T cells in attenuating the allergic airway response following oral treatment with L. reuteri. This potent immuno-regulatory action may have therapeutic potential in controlling the Th2 bias observed in atopic individuals.