As lower respiratory infections are a leading cause of morbidity and mortality worldwide, and have been linked to periodic pandemics, there is a heightened interest in understanding how protective immune cells are mobilized in response to pathogens and contribute to local tissue resistance. The existence of non-recirculating lung resident memory B (BRM) cells was recently defined in an influenza virus infection model and inferred to be protective. Our body of knowledge has since grown significantly, but many unknowns including BRM cell establishment dynamics and requirements for maintenance remain.
We previously used a murine model of serotype-independent immunity against Streptococcus pneumoniae (Sp) to show that resident memory B (BRM) cells are seeded extravascularly in the lung after local bacterial exposures independently of mature tertiary lymphoid structure formation. Using a transgenic mouse model which allowed for the depletion of PD-L2+ memory B cells, we demonstrated that lung PD-L2+ BRM cells directly contribute to clearance of a heterotypic Sp challenge infection, and that their absence correlated with diminished local antibody secreting cell (ASC) activities. Our findings provide evidence of serotype-independent protection mediated by the PD-L2+ BRM cell population and suggest that this is due to their capacity to rapidly differentiate into local ASCs upon memory recall.
We carried out additional studies to elucidate lung B cell population dynamics, locations, and T-dependent requirements for establishment and maintenance after Sp infections. Singular exposure to self-limiting pneumococcal infection was insufficient to generate lasting BRM cells, as well as other heterogeneous extravascular B cell populations which were tracked over time. This included a transient population of proliferatively active lung GC B cells whose accumulation in the lung corresponded with the temporary appearance of organized lymphoid tissue. After an initial respiratory infection was administered to allow for immune priming in the lung and in draining lymph nodes, disruption of T cell interactions during a 2nd infection prevented pan extravascular B cell accumulation and abrogated lung BRM cells.
We posit that our findings are relevant for the development of improved serotype-independent preventative strategies against pneumococcal pneumonia, and all respiratory pathogens in general. Advancing our understanding of tissue-resident B cell populations will aid in the development of next generation vaccines that leverage mucosal memory against respiratory pathogens. / 2025-02-12T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/48084 |
| Date | 12 February 2024 |
| Creators | Etesami, Neelou Shirin |
| Contributors | Mizgerd, Joseph P. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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