Th230 - Transforming Growth factor-β3 Maintains Intestinal Tolerance

Diego Delgado-Zaldivar – Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran; Adrian Albarrán-Godínez – Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran; Sokratis Apostolidis – University of Pennsylvania; Noe Rodriguez-Rodriguez – Medical Research Council, Laboratory of Molecular Biology; Gerardo Suarez-Rojas – Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran; Ximena Barrientos-Suarez – Tecnologico de Monterrey; Ian Bravo-Lee – Tecnologico de Monterrey; H. Benjamin Garcia-Gonzalez – Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran; Abigail de la Cruz – Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran; Diego Cortez – Centro de Ciencias Genomicas, UNAM; Iris Madera-Salcedo – Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran; Florencia Rosetti – Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran; Jose Crispin – Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Abstract Text: Development of inflammatory immune responses towards antigens derived from dietary proteins underlies food allergy and celiac disease. This situation is avoided by oral tolerance, a mechanism through which ingested proteins elicit the differentiation of FoxP3+ regulatory T cells (Tregs) in a TGF-β-dependent manner. In this work, we analyzed the expression of the three TGF-β isoforms and found that TGF-β3 (Tgfb3) was the isoform most abundantly expressed in the small intestine and other barrier tissues. Using isoform-specific neutralizing antibodies and conditional knock-out mice, we provide evidence that supports a fundamental and non-redundant role for TGF-β3 in the establishment of oral tolerance. We demonstrate that, though FoxP3 induction was equivalent when naïve CD4 T cells were activated in the presence of TGF-β1 or TGF-β3, the genetic expression profile of Tregs generated with TGF-β3 differed substantially from that of Tregs induced by TGF-β1. TGF-β3 promoted the expression of gut-homing molecules and a metabolic profile that allowed for rapid functionality and survival. These characteristics were associated with a better capacity to limit intestinal inflammation in an adoptive T cell transfer colitis model. Finally, tamoxifen-induced deletion of Tgfb3 caused the development of severe colitis associated to numerical and functional defects in lamina propria Tregs. Collectively, our results indicate that TGF-β3 is essential for the maintenance of the intestinal immune homeostasis. Its local production is necessary for the establishment of tolerance to oral proteins and its presence is required for the preservation of intestinal health.