Scientists at the Garvan Institute of Medical Research in Sydney, Australia, have identified a previously unknown micro-organ within the immune system, which could lead to new approaches for developing more effective vaccines. Discovered in mice using a live imaging technique known as two-photon microscopy, the thin, flattened structures, given the name subcapsular proliferative foci (SPF),  are located over the surface of draining lymph nodes, and act as a congregation point for immune cells preparing to respond to previously encountered infections. 

Using the 3D microscopy technique, the researchers saw how memory B cells (MBCs) and other immune system cells homed in on the SPF structure, and how the passive MBCs were transformed into activated plasma cells, a population of immune system cell that secretes infection-fighting antibodies against known invaders. “It was exciting to see the memory B cells being activated and clustering in this new structure that had never been seen before,” says Imogen Moran, Ph.D., who is first author on the team’s published paper in Nature Communications. “We could see them moving around, interacting with all these other immune cells and turning into plasma cells before our eyes.” 

Importantly, the researchers also found evidence of similar structures in inflamed lymph nodes from human patients, suggesting that SPF structure and function may be conserved across species. The researchers suggest that their discovery could provide key insights into how the immune system responds to reinfection, which could lead to the development of more effective vaccines. The Garvan Institute scientists, working with colleagues at the University of New South Wales, describe their findings in a paper titled, “Memory B cells are reactivated in subcapsular proliferative foci of lymph nodes.”

Humans have understood the concept of immunity since at least 430 BC, when Greek historian Thucydides recorded that survivors of the Plague of Athens were protected from subsequent reinfection. Early and modern-day vaccines are designed to work by harnessing this power of the immune system to remember previous infections, and mount a fast attack against the invading organism should reinfection occur. “This protection is mediated by neutralizing antibodies secreted by long-lived plasma cells (LLPCs) and by MBCs that proliferate and differentiate more rapidly than naive B cells into antibody-secreting plasma cells upon re-exposure to the antigen,” the authors explain. What hasn’t been understood to date is where the MBCs are localized in the lymph nodes and how they are reactivated to secrete neutralizing antibodies. 

Using a combination of the two-photon microscopy and RNA sequencing in single cells, the Garvan Institute researchers discovered that the reactivated MBCs proliferate and differentiate into plasma cells in the newly discovered SPF. “… imaging and single-cell RNA sequencing confirm that short-lived plasma cells are generated from MBCs in the SPF,” they write. The SPF structures were also found to represent a congregation point for other types of immune cells, and supported T cell-B cell interaction, which is needed for MBCs to differentiate. “This novel structure is enriched for signals provided by T follicular helper cells and antigen-presenting subcapsular sinus macrophages,” the researchers continue. ” … upon antigen recall, MBCs cluster and organize into a novel structure, the SPF, where antigen and T cell help is concentrated to facilitate plasma cell differentiation.”

The SPF structures have evaded discovery until now partly because they only appear when the immune system is preparing to mount an immune response against an infection to which the animal has previously been exposed. And in contrast with live dynamic, two-photon imaging that can view biological structures in 3D as they come and go, traditional microscopy techniques examine thin, 2D slices of chemically fixed tissue.  “So this is a structure that's been there all along, but no one's actually seen it yet because they haven't had the right tools,” says senior author Tri Gian Phan, Ph.D. “It was only when we did two-photon microscopy — which lets us look in three dimensions at immune cells moving in a living animal — that we were able to see these SPF structures forming,” adds Dr. Moran. “It's a remarkable reminder that there are still mysteries hidden within the body — even though we scientists have been looking at the body's tissues through the microscope for over 300 years,” Dr. Phan states.

The discovery will spur further study SPF structure and function to derive new insights into how the immune system functions, and also with a view to improving how we make vaccines, the authors suggest. “These data establish the SPF as the seat of B cell memory … and as an evolutionarily conserved immune response pathway … that may be exploited to rapidly mobilize secondary antibody responses and improve vaccine efficacy.”

“Up until now we have focused on making vaccines that can generate memory B cells,” says Dr. Phan. “Our finding of this new structure suggests that we should now also focus on understanding how those memory B cells are reactivated to make plasma cells, so that we can make this process more efficient.”

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