B resident memory cells in the lungs bear the blueprint to fight the flu and possibly other viral infections

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Immunologists in Australia have eavesdropped on a stowaway population of B cells that hide in the lungs, their telltale biomarkers indicating they’re armed to fight influenza – and their presence yet another sign that the mammalian immune system is still flush with surprises.

Indeed, the immune system is one of the most complex entities known to science, and while much has been learned about its intricacy, aspects of its many functions have yet to be discovered.

Scientists at the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia, have tackled questions that have long vexed immunologists: Does a distinct population of B cells emerge after influenza infection, and if so, are these cells uniquely identified by specific biological signatures? The answers to both questions are resoundingly, “yes.” Yet the institute’s research didn’t end there.

As part of the same group of studies, Australian immunologists also found that these B cells are not only flu-specific, they sequester themselves in the lungs in a residential positioning that allows a strategic advantage. Should flu – or possibly any other respiratory infection – strike in the future, these stowaway B cells can leap into action more efficiently.

“Recent studies have established that memory B cells, largely thought to be circulatory in the blood, can take up long-term residency in inflamed tissues,” explained Dr. Hyon-Xhi Tan, writing in Science Immunology. A large team of investigators from the Peter Doherty Institute for Infection and Immunity worked with researchers from other Australian institutions tracing the fate of B cells to reveal how these vital immune system constituents wind up in the lungs and why they stay there.

The flu-specific B cells, the researchers found, are analogous to the already well-described tissue-resident T cells. The research suggests that B resident memory cells may be special players in B cell immunity. They stay in the lung mucosa to offer a swift response against not only influenza but possibly viral respiratory infections of all kinds.

It is possible, according to Tan and colleagues, that these cells could someday be leveraged through vaccination to combat not just flu, but SARS-CoV-2, respiratory syncytial virus, and other viral pathogens that invade the lungs.

B cells, or B lymphocytes, as they are more precisely known, are part of the highly specific portion of the immune system, which includes T cells. Together, these two broad categories of lymphocytes are at the heart of the adaptive immune response.

The adaptive response is interchangeably known as acquired immunity, or the humoral response, which differs from innate immunity. That broad unrestrained response is mediated by a cascade of cells and proteins. Natural killer cells are part of the innate response, as are cytokines and the explosive, uncontrolled reaction called the cytokine storm.

The innate response, which is present at birth and is the first throughout life to converge on sites of infection or tissue injury, differs from the adaptive. Emerging around the time babies enter the toddler stage, the adaptive immune response is far more targeted and specific.

B cells, for example, can form memories of previous infections and also produce antibodies. Memory B cells recognize antigens from earlier infectious assaults on the body. They differentiate into antibody-producing plasma B cells when the antigen is again encountered and a rapid antibody response is required.

The first time a B cell encounters an antigen, it can take up to 15 days to produce sufficient neutralizing antibodies to quell the pathogen. The second time the same pathogen is encountered, memory B cells, which morph into antibody-producing plasma cells, respond in as few as five days and flood infiltrating pathogens with 100 times more antibodies than during the first encounter.

To find out more about B resident memory cells, Tan and colleagues turned to a mouse model that allowed them to study in intricate detail the origins and activities of B cells that take up residence in the lungs. To seek answers, the Doherty Institute team worked with immunologists and biologists from the Australian Organ and Tissue Authority and the Walter and Eliza Hall Institute of Medical Research, both in Australia.

The stowaway B cells that researchers discovered are located in bronchus-associated lymphoid tissue in the lungs of mice and express the lung residency marker proteins CXCR3, CCR6, and CD69. The team additionally studied human cell lines to further their analyses of these critical cells, and again found resident B cells as stowaways in the lungs.

“These data suggest that B resident memory cells may constitute a discrete component of B cell immunity, positioned at the lung mucosa for rapid humoral response against respiratory viral infections,” Tan wrote in Science Immunology.

The investigators found that B resident memory cells have distinct transcriptional signatures in both mice and humans that differ from regular memory B cells in the blood or spleen.

Resident B cells in the lungs show partial resemblance to memory B cells in lung-draining lymph nodes. Lung-resident memory B cells establish themselves in the lungs after pulmonary influenza and display distinct transcriptional and phenotypic profiles, the research concluded.

“We characterized tissue-resident memory B cells that are stably maintained in the lungs of mice after pulmonary influenza infection,” Tan asserted, “Influenza-specific B resident memory cells were localized within inducible bronchus-associated lymphoid tissues, and displayed transcriptional signatures distinct from classical memory B cells in the blood or spleen while showing partial overlap with memory B cells in lung-draining lymph nodes.”


Humans evolved alongside a vast array of microbial organisms and environmental antigens. Consequently, our immune system is highly adaptable, undergoing long-term systemic and mucosal remodeling following exposure to commonly encountered external stimuli (1).

Traditional specific pathogen–free (SPF) laboratory mice immunologically resemble human infants and lack immune features observed in healthy adults, including resident lymphocytes in nonlymphoid tissues, but gain these more humanlike immune features upon pathogen exposure (1, 2).

Tissue-resident immune cells comprise a group of noncirculating leukocytes that act as a frontline barrier of defense, especially at mucosal sites of constant environmental antigen exposure such as the lung. Although multiple immune cell types, including innate immune cells, may be resident, the long-term protective potential of adaptive memory cells makes resident memory lymphocytes particularly intriguing.

Resident memory T cells (TRM cells) populate mucosal surfaces in response to various bacterial and viral pathogens, and provide rapid local protection against reinfection (3).

In the lung, TRM cells can be maintained in niches independently of organized induced bronchus-associated lymphoid tissue (iBALT, ref. 4). Although TRM cells have been extensively studied over the last 2 decades, it remains uncertain whether complementary resident memory B cells (BRM cells) are a common feature at mucosal sites.

Memory B cells (MBCs) located in mucosal tissues play important roles in mice and humans, but generally are found in organized lymphoid structures such as gut-associated lymphoid tissue (5) and human tonsils/adenoids (6). In the female mouse reproductive tract, herpes simplex virus immunization generates local TRM cells without concurrent BRM cell formation, indicating that the presence of mucosal TRM cells does not always correlate with establishment of a BRM cell pool (7).

Lung BRM cells and lung plasma cells are elicited by influenza infections in mice (8–10). These B cells do not recirculate (8) and provide enhanced protection when adoptively transferred compared with splenic influenza-specific MBCs (10). However, the detailed location of these BRM cells in the lung has not to our knowledge been described. Notably, influenza generates long-lasting iBALT in mice (11).

Like other organized lymphoid structures, iBALT has been shown to support MBCs and plasma cells but is not a typical feature of healthy adult human lungs (12, 13). Lungs of rhesus macaques recovered from asymptomatic H1N1 influenza infection are enriched for TRM but not BRM cells, a finding attributed to the likely lack of iBALT in such low-virulence infections (14). Thus, whether lung BRM and plasma cells are unique to iBALT-containing mouse lungs after influenza or are a common feature of the lung adaptive immune cell landscape remains to be determined.

Both viral and bacterial lung infections impart a large burden of disease globally and in the United States, especially among children and the elderly, for whom pneumonia leads to more deaths than any other infectious disease (15, 16). Streptococcus pneumoniae (pneumococcus), comprising nearly 100 serotypes defined by polysaccharide capsule, represents the most common bacterial cause of community-acquired pneumonia (17).

Nearly all children, even those given pneumococcal vaccination, are colonized or infected multiple times with pneumococcus before the age of 2 years (18). These natural exposures generate serotype-independent (heterotypic) immune protection (19). Heterotypic antibodies, long-lived plasma cells (LLPCs), and lung TRM cells contribute to naturally acquired immunity to pneumococcus (20), but a role for MBCs has yet to be investigated.

Given that virus-elicited MBCs can harbor cross-reactive specificities against mutated viral strains (21, 22), we hypothesized that MBCs may play a similar role in immunity against multiple pneumococcal serotypes. Therefore, we undertook this study to address the fundamental gaps in knowledge regarding the existence of lung-resident B cells outside the setting of influenza-recovered mouse lungs and the contribution of these cells to antibacterial lung immunity.

reference link : https://www.jci.org/articles/view/141810


More information: Hyon-Xhi Tan et al, Lung-resident memory B cells established after pulmonary influenza infection display distinct transcriptional and phenotypic profiles, Science Immunology (2022). DOI: 10.1126/sciimmunol.abf5314

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