Infection of Myeloid Dendritic Cells withListeria monocytogenesLeads to the Suppression of T Cell Function by Multiple Inhibitory Mechanisms

Abstract

Myeloid dendritic cells (DC) and macrophages play an important role in pathogen sensing and antimicrobial defense. In this study we provide evidence that myeloid DC respond to infection with Listeria monocytogenes with simultaneous induction of multiple stimulatory and inhibitory molecules. However, the overall impact of infected DC during T cell encounter results in suppression of T cell activation, indicating that inhibitory pathways functionally predominate. Inhibitory activity of infected DC is effected mainly by IL-10 and cyclooxygenase 2-mediated mechanisms, with soluble CD25 acting as an IL-2 scavenger as well as by the products of tryptophan catabolism. These inhibitory pathways are strictly TNF-dependent. In addition to direct infection, DC bearing this regulatory phenotype can be induced in vitro by a combination of signals including TNF, TLR2, and prostaglandin receptor ligation and by supernatants derived from the infected cells. Both infection-associated DC and other in vitro-induced regulatory DC are characterized by increased resistance to infection and enhanced bactericidal activity. Furthermore, myeloid DC expressing multiple regulatory molecules are identified in vivo in granuloma during listeriosis and tuberculosis. Based on the in vivo findings and the study of in vitro models, we propose that in granulomatous infections regulatory DC may possess dual function evolved to protect the host from disseminating infection via inhibition of granuloma destruction by T cells and control of pathogen spreading.

Role of indoleamine 2,3-dioxygenase in health and disease

“…Although it is ubiquitous throughout the environment, ingestion of Listeria-contaminated food can lead to bacteraemia, infection of the CNS and gastroenteritis in susceptible individuals. IDO1-expressing DCs and macrophages are present in the suppurative granulomas of patients with listeriosis [460] and human monocyte-derived IDO1-expressing DCs have been found to exhibit greater resistance to L. monocytogenes infection and display increased bactericidal activity in vitro [461,462]. This is similar to results observed in human monocyte-derived macrophages, in which L. monocytogenes-induced active IDO1 can also inhibit intracellular infection.…”

Disparity in circulating peripheral blood dendritic cell subsets and cytokine profile of pulmonary tuberculosis patients compared with healthy family contacts

“…Among the DC subsets, mDCs have been considered as crucial for immunity to intracellular pathogens [9], whereas pDCs are important in viral infections [10,11]. As pDCs secrete IFN-␣ and mDCs secrete IL-12, the presence or absence of these subsets during the initiation of an immune response is criti- [26] and healthy family contacts (HFCs) [26].…”

Taking off the brakes: T cell immunity in the liver

“…Comparing the gene expression profile with that of PRRs-stimulated DCs also confirmed the well-recognized notion that different cell types respond with distinct and specific regulation of gene expression. Bioinformatic analysis revealed, however, that TLR4-stimulated LSECs show a transcriptional response more closely related to regulatory rather than immunogenic DCs [76,82]. This provides evidence for common mechanisms employed by LSECs and regulatory DCs to restrict maturation, and to avoid the induction of T cell immunity.…”