Immunosuppressive Property within the Streptococcus pneumoniae Cell Wall That Inhibits Generation of T Follicular Helper, Germinal Center, and Plasma Cell Response to a Coimmunized Heterologous Protein

Abstract

We previously demonstrated that intact, inactivated Streptococcus pneumoniae (unencapsulated strain R36A) inhibits IgG responses to a number of coimmunized soluble antigens (Ags). In this study, we investigated the mechanism of this inhibition and whether other extracellular bacteria exhibited similar effects. No inhibition was observed if R36A was given 24 h before or after immunization with soluble chicken ovalbumin (cOVA), indicating that R36A acts transiently during the initiation of the immune response. Using transgenic cOVA-specific CD4؉ T cells, we observed that R36A had no significant effect on T-cell activation (24 h) or generation of regulatory T cells (day 7) and only a modest effect on T-cell proliferation (48 to 96 h) in response to cOVA. However, R36A mediated a significant reduction in the formation of Ag-specific splenic germinal center T follicular helper (GC Tfh) and GC B cells and antibody-secreting cells in the spleen and bone marrow in response to cOVA or cOVA conjugated to 4-hydroxy-3-nitrophenylacetyl hapten (NP-cOVA). Of note, the inhibitory effect of intact R36A on the IgG anti-cOVA response could be reproduced using R36A-derived cell walls. In contrast to R36A, neither inactivated, unencapsulated, intact Neisseria meningitidis nor Streptococcus agalactiae inhibited the OVA-specific IgG response. These results suggest a novel immunosuppressive property within the cell wall of Streptococcus pneumoniae. During the natural course of bacterial infections, the immune system is exposed to both cell-associated and soluble microbial components (1-3). Distinct differences exist in the immunologic properties between particulate and soluble antigens (Ags) (4-8), suggesting the possibility of cross-regulatory processes occurring upon their simultaneous encounter by the immune system. In addition, the expression of innate stimulating moieties (9, 10), scavenger receptor ligands (11), and virulence factors by intact pathogens may further influence the immune response to coimmunizing soluble antigens. A number of studies in mice have demonstrated inhibitory effects of infectious agents on antibody responses, including germinal center (GC) reactions to soluble protein antigens (12-16). Although the underlying mechanisms of these inhibitory effects were not fully clarified, pathogen-mediated inhibition of dendritic cell (DC) maturation and induction of regulatory T cells (Tregs) were implicated, depending upon the specific pathogen. An understanding of the interplay between intact microbes and immune responsiveness to soluble antigens may have implications on processes involving natural immunity, autoimmunity, and vaccination.We previously demonstrated that intact, heat-killed Streptococcus pneumoniae inhibited the protein-and polysaccharide-specific IgG responses to a number of soluble conjugate vaccines, as well as soluble chicken ovalbumin (cOVA), upon coimmunization of mice intraperitoneally (i.p.) in the presence of alum plus CpG-containing oligodeoxynucleotides (CpG-ODN) as an adjuvant (17). In con...

Immune-responsiveness of CD4+ T cells during Streptococcus suis serotype 2 infection

“…Moreover, it has previously been demonstrated that S. pneumoniae inhibits IgG responses to a number of co-immunized soluble antigens. More precisely, S. pneumoniae was found to mediate a significant reduction in the formation of Ag-specific splenic T follicular helper and germinal center B cells and antibody-secreting cells in the spleen and bone marrow in response to OVA32. Similarly, in a lethal coinfection model of influenza virus and S. pneumoniae , coinfection caused depletion of CD4 + T cells and B cells in mediastinal lymph nodes and spleen, with concomitant reduction in virus-specific antibody responses33.…”

Pneumococcal Surface Protein A Plays a Major Role in Streptococcus pneumoniae–Induced Immunosuppression

“…We observed that Pn strongly suppressed the IgG response to co-immunized, heteroglogous proteins, including chicken ovalbumin (cOVA) (15, 16). Specifically, the inhibition of induction of serum cOVA-specific IgG, in response to i.v.…”

“…Specifically, the inhibition of induction of serum cOVA-specific IgG, in response to i.v. administered cOVA was associated with a marked reduction in the generation of specific CD4+ GC T follicular helper cells (Tfh) and GC B cells in the spleen, and antibody-secreting cells (ASC) in spleen and bone marrow, with no change in the percentages of T regulatory cells and only modest changes in early T cell proliferation (16). We further demonstrated that this inhibitory property was contained within the Pn cell wall.…”

“…However, the identity of the relevant cell wall structure was not determined. Of note, the inhibitory effect of Pn appeared to be Pn-specific, in that neither intact, inactivated Streptococcus agalactiae nor Neissesria meningitis, capsular type C had any effect on the IgG anti-cOVA response (16). …”

Distinct Cellular Pathways for Induction of CD4+ T Cell–Dependent Antibody Responses to Antigen Expressed by Intact Bacteria Versus Isolated Soluble Antigen

“…The process was carried out as described earlier (33). Briefly, RBC-lysed spleen cells from DO11.10 mice (2.5 3 10 7 cells) were incubated in 1 ml 5 mM CFSE (Vybrant CFDA SE; Molecular Probes) in PBS for 10 min at 37˚C.…”