In a paper published in Immunity, the research has for the first time defined the mechanisms that enable resident memory B (BRM) cells to rapidly deliver antibodies at sites infected with the influenza virus.
Tal Arnon, Associate Professor at the Kennedy Institute said: "Resident memory B cells develop in the lungs of influenza-infected hosts. We uncovered a new network of innate-adaptive cell interactions that coordinates the recruitment of BRM cells to infected sites, subsequently leading to the accumulation of plasma cells directly within these regions."
The study, done in close collaboration with Associate Prof. Oliver Bannard at the MRC Human Immunology Unit, used 3D and two-photon microscopy to visualise the BRM cells within the lungs of influenza-virus immune and reinfected subjects. The tissues were rechallenged with the virus and the BRM cells tracked in situ. During the memory phase, prior to reinfection, the cells were sparsely scattered across the alveoli displaying limited migration capabilities. However, within 24hrs after secondary infection, the cells doubled their mean migration speeds, travelled long distances to accumulate at the infected site, and subsequently differentiated into plasma cells.
The process was orchestrated by alveolar macrophages which were important for triggering the expression of chemokines CXCL9 and CXCL10 from infiltrating inflammatory cells. This in turn led to the recruitment of chemokine CXCR3-expressing BRM cells to the infected regions and increased local antibody concentrations.
Influenza is a common airborne virus that infects cells of the respiratory tract. Despite progress in available treatments, it continues to present a significant medical burden and poses the risk of causing global pandemics similar to the one seen in 1918, which was responsible for over 40 million deaths. Ongoing efforts to develop vaccines that induce broadly neutralizing antibodies show encouraging results, but in many cases an important limitation remains the relatively low titers (levels of concentration) that are generated by these vaccines, falling below the threshold needed to saturate infected sites and block viral spreading.
"Given that a single plasma cell can produce up to ~1000 antibodies per second, this process may represent a powerful mechanism to dramatically increase local antibody concentrations where they are needed most; at sites that experience the highest viral titers. The work takes us one step closer to understanding how humoral immunity is regulated locally in peripheral tissues, knowledge that may provide important clues on how to improve the development of effective vaccine strategies to prevent the spread of the flu virus in future."
The research was funded by the Wellcome Trust and Kennedy Trust.