RESUMEN
The mechanisms by which regulatory T (Treg) cells differentially control allergic and autoimmune responses remain unclear. We show that Treg cells in food allergy (FA) had decreased expression of transforming growth factor beta 1 (TGF-ß1) because of interleukin-4 (IL-4)- and signal transducer and activator of transciription-6 (STAT6)-dependent inhibition of Tgfb1 transcription. These changes were modeled by Treg cell-specific Tgfb1 monoallelic inactivation, which induced allergic dysregulation by impairing microbiota-dependent retinoic acid receptor-related orphan receptor gamma t (ROR-γt)+ Treg cell differentiation. This dysregulation was rescued by treatment with Clostridiales species, which upregulated Tgfb1 expression in Treg cells. Biallelic deficiency precipitated fatal autoimmunity with intense autoantibody production and dysregulated T follicular helper and B cell responses. These results identify a privileged role of Treg cell-derived TGF-ß1 in regulating allergy and autoimmunity at distinct checkpoints in a Tgfb1 gene dose- and microbiota-dependent manner.
Asunto(s)
Autoinmunidad/inmunología , Hipersensibilidad/inmunología , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta1/inmunología , Adolescente , Animales , Autoinmunidad/genética , Linfocitos B/inmunología , Diferenciación Celular , Niño , Preescolar , Hipersensibilidad a los Alimentos/inmunología , Dosificación de Gen , Humanos , Hipersensibilidad/genética , Inmunoglobulina G/inmunología , Lactante , Mastocitos/inmunología , Ratones , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Células T Auxiliares Foliculares/inmunología , Linfocitos T Reguladores/metabolismo , Transcripción Genética , Factor de Crecimiento Transformador beta1/genética , Adulto JovenRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
The role of dysbiosis in food allergy (FA) remains unclear. We found that dysbiotic fecal microbiota in FA infants evolved compositionally over time and failed to protect against FA in mice. Infants and mice with FA had decreased IgA and increased IgE binding to fecal bacteria, indicative of a broader breakdown of oral tolerance than hitherto appreciated. Therapy with Clostridiales species impacted by dysbiosis, either as a consortium or as monotherapy with Subdoligranulum variabile, suppressed FA in mice as did a separate immunomodulatory Bacteroidales consortium. Bacteriotherapy induced expression by regulatory T (Treg) cells of the transcription factor ROR-γt in a MyD88-dependent manner, which was deficient in FA infants and mice and ineffectively induced by their microbiota. Deletion of Myd88 or Rorc in Treg cells abrogated protection by bacteriotherapy. Thus, commensals activate a MyD88/ROR-γt pathway in nascent Treg cells to protect against FA, while dysbiosis impairs this regulatory response to promote disease.