SLy2 controls the antibody response to pneumococcal vaccine through an IL‐5Rα‐dependent mechanism in B‐1 cells

Abstract

The adaptor protein SLy2 (Src homology domain 3 lymphocyte protein 2) is located on human chromosome 21 and was reported to be among a group of genes amplified in Down's syndrome (DS) patients. DS patients characteristically show an impaired immunity to pneumococcal infections. However, molecular mechanisms linking gene amplifications with specific DS phenotypes remain elusive. To investigate the effect of SLy2 gene amplification on the mammalian immune system, we studied SLy2 overexpressing transgenic-SLy2 (TG) mice. We found that baseline immunoglobulin M (IgM) levels as well as IgM responses following Pneumovax immunizations were reduced in TG mice. Moreover, B-1 cells, the major natural IgM-producing population in mice, were reduced in the peritoneal cavity of TG mice, while other immune cell compartments were unaltered. Mechanistically, SLy2 overexpression attenuated the expression of the IL-5 receptor α chain on B-1 cells, resulting in decreased B-1 cell numbers and decreased differentiation into Ab-secreting cells. Since B-1 cells essentially contribute to immunity against Streptococcus pneumoniae, the present study provides a novel molecular link between SLy2 expression and pneumococcal-specific IgM responses in vivo. These studies suggest that the adaptor protein SLy2 is a potential future target for immunomodulatory strategies for pneumococcal infections.

SLy2‐deficiency promotes B‐1 cell immunity and triggers enhanced production of IgM and IgG2 antibodies against pneumococcal vaccine

“…We previously reported decreased frequencies of B-1 cells and pPS-specific antibodies in SLy2overexpressing mice, identifying SLy2 as an immunoinhibitory adapter protein. 10 To analyze the impact of SLy2-deficiency on immune cell subsets and responses, we have generated Ko mice, globally lacking the expression of SLy2 ( Figure S1). On the basis of earlier findings, we expected improved B-1 cell immunity in the absence of SLy2.…”

“…Moreover, SLy2 overexpression attenuates interleukin (IL) 5-dependent antibody production of stimulated B-1 cells in vitro. 10 B-1 cells constitute an innate-like B-cell population, phenotypically and functionally differing from conventional (B-2) B cells. They are mainly localized in the peritoneal and pleural cavity, possess the ability of selfrenewal, and display a limited repertoire of B-cell receptor specificities.…”

“…Indeed, when immunized with the pneumococcal vaccine, SLy2-Tg mice show significantly impaired antibody responses towards pneumococcal polysaccharides (pPS). 10 Routine vaccinations of adults with the polysaccharide vaccine Pneumovax 23 (P23) and children with the conjugate-vaccine Prevenar 13 (PCV13) promote herd immunity against S. pneumoniae by reducing nasopharyngeal colonization within the population. However, immune responses to pneumococcal vaccine decline with increasing age, and the overall efficacy of immunization in preventing adult pneumococcal lung infection is estimated to be weak.…”

SLy1 regulates T‐cell proliferation during Listeria monocytogenes infection in a Foxo1‐dependent manner

“…SLy1 and SLy2 are highly homologous, as both express a bipartite nuclear localization sequence as well as an SH3 and an SAM domain [11,14]. SLy2, also called HACS1, SAMSN1, and NASH1, regulates the immune response via interaction with transcription factors [15][16][17]. Similar to SLy2, SLy1 was shown to be involved in immune regulation and plays an important role during T-cell development [14,18].…”

HACS1 signaling adaptor protein recognizes a motif in the paired immunoglobulin receptor B cytoplasmic domain

“…Since that discovery, HACS1 has been recognized further in blood vessel development 1 and the progression of cancers with aggressive phenotypes 2,3 . By virtue of its location on chromosome 21, there is interest in exploring the role of HACS1 in Down's syndrome 4,5 and late-onset Alzheimer's disease 5,6 . Sequence analysis of human HACS1 and its homolog, HACS2/SLy1 [7][8][9][10][11] , reveal juxtaposed SAM 12 and SH3 13 domains that are wellknown mediators of protein-protein interactions.…”