Systems vaccinology approaches have been used to successfully define early signatures of the vaccine-induced immune response. However, the possibility that transcriptomics can also identify a correlate/surrogate for vaccine inflammation has not been fully explored. We have compared four licensed vaccines with known safety profiles, and three agonists of TLRs with known inflammatory potential, to elucidate the transcriptomic profile of an acceptable response to vaccination versus an inflammatory reaction. In mice, we looked at the transcriptomic changes in muscle at the injection site, the lymph node that drained the muscle and the PBMC isolated from the circulating blood from 4 hours and over the period of one week. A detailed examination and comparative analysis of these transcriptomes revealed a set of novel biomarkers reflective of inflammation after vaccination. These biomarkers are readily measurable in the peripheral blood, providing useful surrogates of inflammation, as a way to select candidates with acceptable safety profiles.
Complete microarray data was deposited in NCBI's Gene Expression Omnibus and is accessible through GEO accession number GSE120661.
Identification of Biomarkers of Vaccine Reactogenicity:NCBI Gene Expression Omnibus, GSE120661.
- Paul F McKay
- Deniz Cizmeci
- Yoann Aldon
- Jeroen Maertzdorf
- January Weiner
- Stefan HE Kaufmann
- David JM Lewis
- Robert A van den Berg
- Guiseppe Del Giudice
- Robin J Shattock
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: The animal studies were approved by the Ethical Review Board of Imperial College London where the experiments were carried out and work was performed in strict compliance with project and personal animal experimentation licences granted by the UK government in accordance with the Animals in Scientific Procedures Act (1986)- PPL 70-7457 Protocol #1. Animals received minimal handling and their physical condition was monitored at least twice daily. All procedures were performed under isoflurane anaesthesia when appropriate, and all efforts were made to minimise suffering. There was a detailed protocol in place, as per requirement of the humane endpoints described in the animal licence, for early euthanasia in the event of onset of illness or significant deterioration in condition. At the end of the experiment all animals were culled using a schedule 1 method and death confirmed before necropsy. Food and water were supplied ad libitum.
- Urszula Krzych, Walter Reed Army Institute of Research, United States
© 2019, McKay et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Notch-RBP-J signaling plays an essential role in the maintenance of myeloid homeostasis. However, its role in monocyte cell fate decisions is not fully understood. Here, we showed that conditional deletion of transcription factor RBP-J in myeloid cells resulted in marked accumulation of blood Ly6Clo monocytes that highly expressed chemokine receptor CCR2. Bone marrow transplantation and parabiosis experiments revealed a cell-intrinsic requirement of RBP-J for controlling blood Ly6CloCCR2hi monocytes. RBP-J-deficient Ly6Clo monocytes exhibited enhanced capacity competing with wildtype counterparts in blood circulation. In accordance with alterations of circulating monocytes, RBP-J deficiency led to markedly increased population of lung tissues with Ly6Clo monocytes and CD16.2+ interstitial macrophages. Furthermore, RBP-J deficiency-associated phenotypes could be genetically corrected by further deleting Ccr2 in myeloid cells. These results demonstrate that RBP-J functions as a crucial regulator of blood Ly6Clo monocytes and thus derived lung-resident myeloid populations, at least in part through regulation of CCR2.
T cells are crucial for efficient antigen-specific immune responses and thus their migration within the body, to inflamed tissues from circulating blood or to secondary lymphoid organs, plays a very critical role. T cell extravasation in inflamed tissues depends on chemotactic cues and interaction between endothelial adhesion molecules and cellular integrins. A migrating T cell is expected to sense diverse external and membrane-intrinsic mechano-physical cues, but molecular mechanisms of such mechanosensing in cell migration are not established. We explored if the professional mechanosensor Piezo1 plays any role during integrin-dependent chemotaxis of human T cells. We found that deficiency of Piezo1 in human T cells interfered with integrin-dependent cellular motility on ICAM-1-coated surface. Piezo1 recruitment at the leading edge of moving T cells is dependent on and follows focal adhesion formation at the leading edge and local increase in membrane tension upon chemokine receptor activation. Piezo1 recruitment and activation, followed by calcium influx and calpain activation, in turn, are crucial for the integrin LFA1 (CD11a/CD18) recruitment at the leading edge of the chemotactic human T cells. Thus, we find that Piezo1 activation in response to local mechanical cues constitutes a membrane-intrinsic component of the ‘outside-in’ signaling in human T cells, migrating in response to chemokines, that mediates integrin recruitment to the leading edge.