SLy2-overexpression impairs B-cell development in the bone marrow and the IgG response towards pneumococcal conjugate-vaccine.

Background: Infections with Streptococcus pneumoniae can cause severe diseases in humans including pneumonia. Although guidelines for vaccination have been established, S. pneumoniae is still responsible for a serious burden of disease around the globe. Currently, two pneumococcal immunizations are available, namely the pure polysaccharide vaccine Pneumovax23 (P23) and the conjugate-vaccine Prevenar13 (PCV13). We recently reported impaired thymus-independent antibody responses towards P23 in mice overexpressing the immunoinhibitory adapter SLy2. The purpose of this study was to evaluate adaptive B-cell responses towards the thymus-dependent vaccine PCV13 in SLy2-overexpressing mice and to study their survival rate during pneumococcal lung infection. Moreover, we investigated B-cell developmental stages within the bone marrow (BM) in the context of excessive SLy2-expression.

Methods: B-cell subsets and their surface immune globulins were investigated by flow cytometry. For class-switch assays, isolated splenic B cells were stimulated in vitro with lipopolysaccharide and interleukin-4 and antibody secretion was quantified via LEGENDplex. To study PCV13-specific responses, mice were immunized and serum antibody titers (immunoglobulin M, immunoglobulins IgG , IgG , and IgG ) were examined by enzyme-linked immunosorbent assay. Survival rates of mice were assessed within 7 days upon intranasal challenge with S. pneumoniae.

Results: Our data demonstrate impaired IgG and IgG antibody responses towards the pneumococcal conjugate-vaccine PCV13 in SLy2-overexpressing mice. This was accompanied by reduced frequencies and numbers of BM-resident plasmablasts. In addition, we found drastically reduced counts of B-cell precursors in the BM of SLy2-Tg mice. The survival rate upon intranasal challenge with S. pneumoniae was mostly comparable between the genotypes.

Conclusion: Our findings demonstrate an important role of the adapter protein SLy2 in the context of adaptive antibody responses against pneumococcal conjugate-vaccine. Interestingly, deficits in humoral immunity seemed to be compensated by cellular immune effectors upon bacterial challenge. Our study further shows a novel relevance of SLy2 for plasmablasts and B-cell progenitors in the BM.