Targeted delivery of regulatory macrophages to lymph nodes interferes with Tcell priming by preventing the formation of stable immune synapses.

Abstract

Immunosuppressive myeloid cells are frequently induced in tumors and attenuate anti-tumor effector functions. In this study, we differentiate immunosuppressive regulatory macrophages (Mregs) from hematopoietic progenitors and test their potential to suppress adaptive immune responses in lymph nodes. Targeted delivery of Mregs to lymph nodes is facilitated by retroviral overexpression of the chemokine receptor CCR7 and intra-lymphatic cell application. Delivery of Mregs completely abolishes the priming of cognate CD8 cells and strongly reduces delayed-type hypersensitivity reactions. Mreg-mediated Tcell suppression requires cell-cell contact-regulated nitric oxide production. Two-photon microscopy reveals that nitric oxide produced by Mregs reduces the interaction duration between dendritic cells and Tcells. Exposure of activated Tcells to nitric oxide strongly reduces their binding to ICAM-1, indicating that nitrosylation of proteins involved in cell adhesion affects synapse formation. Thus, this study identifies a mechanism of myeloid cell-mediated immune suppression and provides an approach for its therapeutic use.