Lower respiratory tract infections, like those caused by influenza A virus (IAV) and respiratory syncytial virus (RSV), and the pneumonia they cause are a global health concern and burden. Infection and vaccination induce immune memory responses that are vital for neutralizing and resolving subsequent infections. B cells play a substantial role in preventing reinfection. They exert their effects through several functions but most appreciably via anti-viral antibody secretion. B cells, as is the case with other immune cells, possess several subsets, each with defined roles and functions. The B7 protein family surface receptors CD80 and PD-L2 have been identified as distinguishing two populations based on their presence or absence on B cells: CD80-PD-L2- (double negative, DN) and CD80+PD-L2+ (double positive, DP). In the spleen, DN cells have relatively low mutation frequencies, antigen specificity, and tend to enter the germinal center reaction. On the other hand, DP cells have a more mutated B cell receptor, increased antigen-specificity, and differentiate into antibody secreting cells upon restimulation. It remains unclear if these two populations are related, what differences, if any, they possess from each other, cellular crosstalk required for their maintenance, and their roles in immunity against IAV reinfection. Additionally, it is not known if local B cells (i.e. DN and DP) in the lung are distinct from those in the spleen or if they are a homogenous population. Our work was aimed at investigating these gaps in the field.
We showed that IAV infection results in the accumulation of extravascular DP B cells in the murine lung. B cells in general appear to localize near sites of previous infection in organized lymphoid-like structures. Naphthalene-mediated club cell ablation results in the partial loss of the lung DP cell population while DN cells appear unaffected, suggesting the lung epithelium plays a role in the maintenance of the DP cells. DP cells possess more of the IAV-specific cells than the DN cells suggesting an anti-viral role. In part, the DP cells originate from DN predecessors and possess a unique V gene profile. During the immune reaction, DN cells differentiate into DP cells and, on occasion, revert. The DN cell population in the lung is largely distinct from that found in the spleen, suggesting that these cells originate from a secondary lymphoid tissue. Finally, we have engineered a recombinant RSV containing a cre-recombinase transgene that replicated with similar kinetics to the parental strain. This novel tool will allow us to examine qualities of cells previously infected with RSV and investigate any role they may play in immune maintenance and/or lung health.
To conclude, we outline major differences between two populations of B cells of considerable immune interest, show how they may rely, in part, on epithelial cells in the lung, and develop a new tool to investigate these topics in other respiratory viruses of public health concern. / 2024-11-02T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/47437 |
| Date | 02 November 2023 |
| Creators | Breen, Michael Patrick |
| Contributors | Fearns, Rachel, Mizgerd, Joseph P. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution 4.0 International, http://creativecommons.org/licenses/by/4.0/ |
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