Transcriptional specialization of human dendritic cell subsets in response to microbial vaccines

Romain Banchereau,Alma-Martina Cepika,Yuanyuan Wang,Sangkon Oh,Ingrid Gayet,Damien Chaussabel,Derek Blankenship,Shruti Athale,Virginia Pascual,Abhilasha Cheruku,Jacques Banchereau,Marina Ohouo,Nicole Baldwin,Octavio Ramilo,Yaming Xue,Karolina Palucka,Isabelle Berthier,Gerlinde Obermoser,Hui Xu,Patrick Metang,Lu Ann Snipes ,Chun I Yu

doi:10.1038/ncomms6283

Romain Banchereau, Alma-Martina Cepika + Show 20 more

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https://doi.org/10.1038/ncomms6283

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The mechanisms by which microbial vaccines interact with human APCs remain elusive. Herein, we describe the transcriptional programs induced in human DCs by pathogens, innate receptor ligands and vaccines. Exposure of DCs to influenza, Salmonella enterica and Staphylococcus aureus allows us to build a modular framework containing 204 transcript clusters. We use this framework to characterize the responses of human monocytes, monocyte-derived DCs and blood DC subsets to 13 vaccines. Different vaccines induce distinct transcriptional programs based on pathogen type, adjuvant formulation and APC targeted. Fluzone, Pneumovax and Gardasil, respectively, activate monocyte-derived DCs, monocytes and CD1c+ blood DCs, highlighting APC specialization in response to vaccines. Finally, the blood signatures from individuals vaccinated with Fluzone or infected with influenza reveal a signature of adaptive immunity activation following vaccination and symptomatic infections, but not asymptomatic infections. These data, offered with a web interface, may guide the development of improved vaccines.

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The mechanisms by which microbial vaccines interact with human antigen-presenting cells (APCs) remain elusive
These include CD1c þ dendritic cells (DCs), which are equipped with a wide range of pattern recognition receptors (PRRs) and are good inducers of both CD8 þ and CD4 þ T-cell responses; CD141 þ DCs, which efficiently crosspresent necrotic and non-self antigens to CD8 þ T cells; plasmacytoid DCs, which secrete large amounts of type-I interferon (IFN) on challenge with viruses and nucleic acids; and monocyte-derived inflammatory DCs, which can be found in tissues under certain inflammatory conditions[14,15,16]
Principal variance component analysis (PVCA) combined with further cluster analysis demonstrated that the main contributor to transcriptional profile heterogeneity is the type of pathogen, that is, virus or bacteria followed by time point and population

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The mechanisms by which microbial vaccines interact with human APCs remain elusive. we describe the transcriptional programs induced in human DCs by pathogens, innate receptor ligands and vaccines. DC transcriptional programs at steady state or in response to various pathogen-associated molecular patterns have been examined in vitro and in vivo, using combinations of microarrays and small interfering RNA in mammalian cells[41,42,43,44,45] The interpretation of these complex data sets has been simplified by dimension-reducing approaches such as gene co-expression module frameworks[46]. Systems vaccinology has emerged[47,48,49,50] as a discipline that leverages systems biology approaches to study the mechanisms of action of vaccines, and identify immunological correlates of protection Despite these efforts, a significant gap of knowledge remains in the understanding of how vaccines interact with human DC subsets, and how this leads to the development of protective immunity. We applied this framework to characterize the early response of human DCs and their precursors to 13 microbial vaccines, thereby identifying common and specific transcriptional networks to each pathogenic challenge

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