Vaccines against respiratory diseases are injected into muscles and do not directly activate memory immune cells in the lungs, that mount a rapid immune response. Triggering populations of memory B lymphocytes in the lungs could increase the efficacy of vaccines against viral respiratory diseases such as influenza and COVID-19, a new study shows.
The study, conducted by scientists from INSERM, CNRS and Aix-Marseille University at the Center of Immunology Marseille-Luminy in France, was published in an article in the journal Immunity “Viral infection engenders bona fide and bystander subsets of lung-resident memory B cells through a permissive mechanism” on June 28, 2022. The findings could help improve the efficacy of influenza or COVID-19 vaccines through intranasal administrations.
“The hypothesis is that by intranasal vaccination, we could mimic the natural entry pathway of the virus, mobilize these lung memory B cells to block the virus as soon as it reaches the respiratory tract in the event of an infection. In this way, we could combat severe forms and better protect against infection,” said Gaya.
Infections trigger the generation of long-lasting memory B cells in lymph nodes and the spleen, that are mobilized to mount a rapid immune attack if the body encounters the same infectious agent again. Recent studies have shown that memory B cells can also be found in the lungs and provide localized protection against respiratory infections.
In the current study, researchers led by Mauro Gaya, PhD, a scientist at INSERM, explain the nature and function of memory B immune cells in the lung and clarify their role in long-term immunity against respiratory infections using mouse models infected with influenza and SARS-CoV-2 viruses.
“We combined influenza and SARS-CoV-2 infection with fluorescent-reporter mice to identify memory B cells regardless of antigen specificity,” the authors explained. Upon tracking the appearance of memory B cells after infection using the fluorescent reporter, the researchers conducted gene expression analysis in individual cells (single-cell transcriptome analysis). “These techniques enabled us to precisely localize these cells in the lungs of our animal models and describe their gene expression profile cell by cell to study their function,” said Gaya.
Following the clearance of the viruses from the body, the authors found clusters of memory B cells located strategically in the bronchial mucous membrane. Localizing in the bronchial wall ensures that these cells encounter any virus entering the lungs with the breath.
Single-cell transcriptomics revealed two distinct subsets of memory B cells in the bronchial niche. The authors call these “bona fide” or “bystander” memory B cells. These subsets express different genes and arise from different ancestral progenitor cells through different mechanisms. For example, whereas both bona fide and bystander memory B cells express the genetic marker CCR6, only bona fide memory B cells express the genetic marker CXCR3.
Bona fide memory B cells harbor a direct affinity for the virus that triggered their generation. When they encounter the virus again, they rapidly differentiate into plasma B cells that produce antibodies targeted against the virus. Bystander memory B cells, that develop through an alternative permissive mechanism and can represent up to half the total pool of memory B cells generated upon infection, have no direct affinity for the virus that triggered their generation. However, they retain the ability to display antigens on their surface in the form of immune complexes and therefore can still bind the virus through the antibodies produced by the bona fide memory B cells.
“We have a two-tier system that enables a synergistic effect and increases the efficacy of the anti-viral memory response in the lungs,” said Gaya.
Gaya’s team proposes, the prevalence of bystander memory B cells with no specificity for the infecting pathogen expands the diversity of the initial B cell repertoire. In addition, by maintaining immune complexes near bona fide memory B cells, they enable cross-reactions of different bona fide memory B cell populations against several types of viruses, enhancing the intensity of the humoral immune attack.