A breath of fresh air. Better vaccines for COVID-19, the flu, tuberculosis, and whooping cough.

David Pejoski, Marie Ballester, Floriane Auderset, Maria Vono, Dennis Christensen, Peter Andersen, Paul-Henri Lambert, Claire-Anne Siegrist

Overview

Why do intranasal or intrapulmonary (inhaled) vaccines induce more protective immune responses in mucosal airway tissue compared to injectable vaccines? Vaccinologists noticed a long time ago that the route of vaccine administration has a huge impact on the type and anatomical location of the immune response generated. They figured out that when T cells are primed in the presence of vitamin A or vitamin D, they then preferentially traffic into the gut and skin respectively. However, until relatively recently, the molecular mechanisms that instruct T cells to home to the lung have been largely unknown.

Summary

The ability to induce pulmonary immune responses via vaccination is a prized goal for developers of vaccines against respiratory illnesses. Many mucosal route vaccines already have this ability, yet injectable routes - the historical gold-standard vaccination approach, appear to be preferred by regulators, consumers, and industry. This may be because of the real and perceived advantages of parenteral routes, including enhanced dose precision, safety, but also simply as a means of avoiding costly marketing and scientific 'proof of concept' safety studies to address consumer hesitance and strict drug approval regulations associated with novel technologies. Therefore, through an understanding of the molecular signals that tell T cells to reside in or traffic into the lung, we would be able to design injectable vaccines that elicit enhanced immunity against respiratory pathogens, such as Mycobacterium tuberculosis (TB), Bordetella pertussis (whooping cough), seasonal or pandemic influenza A virus (flu), or coronavirus infections (MERS, SARS-CoV-19; COVID-19). This Pubfacts Showcase article reflects my own opinions about our open-access research paper, available here: https://www.frontiersin.org/articles/10.3389/fimmu.2019.01650/full

Author Comments

David Pejoski, Ph.D.
David Pejoski, Ph.D.
University of Geneva
Maître Assistant / Postdoctoral Researcher
Immunology
Geneva | Switzerland
Our study identified phenomena that contribute to: the induction of lung-trafficking molecules on T cells (‘T cell imprinting’), and the overall output of tissue-tropic T cells in vivo. The main conceptual advance is that induction of tissue- trafficking molecule expression that enhances CD4+ T cell homing to the lung in vivo can be augmented by surface molecules interactions with in vivo-matured CD11b+ dendritic cells (DCs). Prior literature has focused on soluble factors produced by DCs, CD103+ DC subsets, CD8+ T cell priming, and often employed in vitro-matured DCs. We also show that DC surface molecule signatures are site-specific. For example, lung-draining lymph nodes (LNs) DCs are richer in several costimulatory molecules, which resulted in enhanced CD4+ T cell priming capacity (per DC) compared to intramuscular draining LN DCs. The enhancement was in terms of general T cell activation and specific lung-homing T cell output. Finally, the density of potent lung-imprinting phenotype DCs in the dLNs varies depending on the route of immune stimulation, and represents an additional factor that quantitatively influences the tissue-tropic T cell response. These findings therefore demonstrate that surface costimulatory events could be harnessed to modulate the tissue-trafficking receptor profiles of prophylactic or therapeutic T cell interventions. David Pejoski, Ph.D.

Resources

Free access - original research article
https://www.frontiersin.org/articles/10.3389/fimmu.2019.01650/full

Site-Specific DC Surface Signatures Influence CD4 T Cell Co-stimulation and Lung-Homing.

Authors:
David Pejoski, Ph.D.
David Pejoski, Ph.D.
University of Geneva
Maître Assistant / Postdoctoral Researcher
Immunology
Geneva | Switzerland

Front Immunol 2019 18;10:1650. Epub 2019 Jul 18.

Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Dendritic cells (DCs) that drain the gut and skin are known to favor the establishment of T cell populations that home to the original site of DC-antigen (Ag) encounter by providing "imprinting" signals to T cells in the lymph node (LN). To study the induction of lung T cell-trafficking, we used a protein-adjuvant murine intranasal and intramuscular immunization model to compare -activated Ag DCs in the lung and muscle-draining LNs. Higher frequencies of Ag CD11b DCs were observed in lung-draining mediastinal LNs (MedLN) compared to muscle-draining inguinal LNs (ILN). Ag CD11b MedLN DCs were qualitatively superior at priming CD4 T cells, which then expressed CD49a and CXCR3, and preferentially trafficked into the lung parenchyma. CD11b DCs from the MedLN expressed higher levels of surface podoplanin, Trem4, GL7, and the known co-stimulatory molecules CD80, CD86, and CD24. Blockade of specific MedLN DC molecules or the use of sorted DC and T cell co-cultures demonstrated that DC surface phenotype influences the ability to prime T cells that then home to the lung. Thus, the density of dLN Ag DCs, and DC molecule signatures are factors that can influence the output and differentiation of lung-homing CD4 T cells.

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Source
http://dx.doi.org/10.3389/fimmu.2019.01650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668556PMC
July 2019
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