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.
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
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.
Front Immunol 2019 18;10:1650. Epub 2019 Jul 18.
Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
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