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

Abstract

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 IgG1, IgG2, and IgG3) 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 IgG1 and IgG3 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.

The emerging and diverse roles of the SLy/SASH1‐protein family in health and disease—Overview of three multifunctional proteins

“…Complementary, the expression of SLy2 is reduced in human myeloma cell lines as well as MM patient‐derived CD138 + plasma cells as compared to healthy controls 79 . Intriguingly, novel findings of our group revealed significantly decreased rates and absolute numbers of BM‐resident CD138 + TACI + plasmablasts in SLy2‐overexpressing mice 67 . In conjunction, these data allow speculating that SLy2 might serve as a negative regulator of plasma cell differentiation/ proliferation.…”

“…62 Fittingly, novel research findings have revealed drastically reduced counts of B cell progenitors within the BM of SLy2-overexpressing mice. 67 These observations apply to several developmental stages, including pro-B, pre-B, and immature B cells. This is of high interest, since various studies have reported defects in early development and expansion of B cells in DS children during their first year of life.…”

“…Fittingly, novel research findings have revealed drastically reduced counts of B cell progenitors within the BM of SLy2‐overexpressing mice 67 . These observations apply to several developmental stages, including pro‐B, pre‐B, and immature B cells.…”

“…79 Intriguingly, novel findings of our group revealed significantly decreased rates and absolute numbers of BM-resident CD138 + TACI + plasmablasts in SLy2-overexpressing mice. 67 In conjunction, these data allow speculating that SLy2 might serve as a negative regulator of plasma cell differentiation/ proliferation. Inspired by these results, SLy2 should be examined in the context of signaling pathways related to master regulators of plasma cell differentiation such as Blimp-1 and XBP-1.…”