Peripheral tolerance orchestrated by regulatory T cells, dendritic cells (DCs), and mast cells (MCs) has been studied in several models including skin allograft tolerance. We now define a role for MCs in controlling DC behavior (" conditioning" ) to facilitate tolerance. Under tolerant conditions, we show that MCs mediated a marked increase in tumor necrosis factor (TNFα)-dependent accumulation of graft-derived DCs in the dLN compared to nontolerant conditions. This increase of DCs in the dLN is due to the local production of granulocyte macrophage colony-stimulating factor (GM-CSF) by MCs that induces a survival advantage of graft-derived DCs. DCs that migrated to the dLN from the tolerant allograft were tolerogenic; i.e., they dominantly suppress T cell responses and control regional immunity. This study underscores the importance of MCs in conditioning DCs to mediate peripheral tolerance and shows a functional impact of peripherally produced TNFα and GM-CSF on the migration and function of tolerogenic DCs.
Bibliographical noteFunding Information:
The authors acknowledge support of National Institutes of Health grant (R01AT005382, AI048667, United States), “The Wellcome Trust,” MRC Centre for Transplantation (United Kingdom), National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at Guy's and St Thomas' NHS Foundation Trust and King's College London and the Agency of Science, Technology and Research (A ∗ STAR, Singapore). E.C.N. is supported by a postdoctoral fellowship from National Multiple Sclerosis Society. C.O. is recipient of a postdoctoral fellowship from BECAS Chile.