The thymus-independent immunity conferred by a pneumococcal polysaccharide is mediated by long-lived plasma cells

Abstract

It was recently shown that bacterial thymus-independent (TI) antigens confer long-lasting immunity and generate memory B lymphocytes. However, reactivation of TI memory B cells is repressed in immunocompetent mice, thus raising the issue of the mechanism whereby TI vaccines confer immune protection. Here, we propose an explanation to this apparent paradox by showing that a Streptococcus pneumoniae capsular polysaccharide (PS) generates long-lived bone marrow (BM) plasma cells which frequency can be increased by CpG oligodeoxynucleotides (ODNs). The adjuvant effect of CpG ODNs on the PS3 Ab response is directly targeted to B cells and does not involve B-1a cells. We also demonstrated that BM plasma cells generated in response to the thymus-dependent (TD) form of the PS vaccine have a higher secretion capacity than those produced after immunization with the CpGadjuvanted PS vaccine. Finally, we show that the PS-specific BM plasma cell compartment is sufficient to confer full protection of vaccinated mice against S pneumoniae infection. Altogether, our results show that TI antigens like their TD counterparts can generate both the lymphoid and the plasma cell component of B-cell memory. They also provide a framework for the improvement and widespread usage of TI vaccines. IntroductionDespite advances in antimicrobial therapy, infections with extracellular polysaccharide (PS)-encapsulated bacteria remain an important clinical problem and a primary source of death worldwide. Pathogenic bacteria including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae express capsular PSs that behave as prototypic thymus-independent (TI) antigens (Ags). These Ags have initially been defined on the basis of their ability to elicit an antibody (Ab) response in T cell-deficient or athymic mice by a mechanism that requires expression of a functional Bruton tyrosine kinase. 1 They are mostly nonpeptidic molecules, which in their great majority, are unable to follow the conventional Agprocessing pathway leading to presentation by MHC class I and II molecules. 2 To overcome systemic infections by encapsulated extracellular bacteria such as S pneumoniae, B cells rapidly generate a protective Ab response against capsular PS. B-1 and marginal zone B cells have been envisioned as key players in the humoral response against TI Ags. 3 More recently, 2 studies, using Borrelia hermsii or capsular PSs from S pneumoniae as immunogens, have shown that B-1b cells are critically involved in bacterial clearance in vaccinated mice. 4,5 It has long been thought that the generation of memory B cells is restricted to thymus-dependent (TD) responses. However, the recent observation that adoptive transfer of B-1b cells from donor mice immunized with whole bacteria can confer long-lasting TI immunity to immunodeficient mice shows that TI Ags generate B-cell memory and that this function can be assigned to the B-1b-cell subset. 5 Nonetheless, the concept of TI B-cell memory is at odds with the fact that, unlike TD Ags, TI Ags fail to...

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

“…1 proportionally to the maximum life span of humans, which is 122 y (69). An excellent example of the temporal appearance of shortlived plasmablasts in secondary lymphoid tissue and long-lived plasma cells in the bone marrow can be found in a study by Taillardet et al (68). Although this study uses mice, we have calculated that one mouse month is equivalent to ∼2.6 human years [based on a 4-y maximum life span (70)]; thus, the relative appearances of the three phases of circulating antibody and concomitant emergence of plasmablasts and plasma cells are in reasonable agreement between the two species.…”

Background paper to the updated pneumococcal vaccination recommendation for older adults in Germany

“…However, various studies have shown that PPS induce efficient activation of IgM + memory B cells (IgM + IgD + CD27 + ) and generation of long-lived plasma cells (CD38 + CD20 low ). This is accompanied by the generation and persistence of IgM and IgG antibodies against PPS [101][102][103][104][105][106][107][108]. IgM + memory B cells circulating in the blood are the peripheral correlates of the marginal zone B cells of the spleen.…”

Low hemagglutinin antigen dose influenza vaccines adjuvanted with AS03 alter the long-term immune responses in BALB/c mice

“…However, ASC spot size was investigated following vaccination of a novel measles vaccine in mice, 30 and ASC spot size was found to vary following Streptococcus pneumoniae polysaccharide vaccination in mice with the presence or absence of a protein conjugate. 31 In the latter study, Taillardet et al demonstrated that the thymus-dependent, tetanus toxoid-polysaccharide conjugate formulation generated BM plasma cells with greater antibody secretion compared to a thymus-independent polysaccharide vaccine given with CpG adjuvant. 31 That study concluded that plasma cells activated by the different types of vaccines were functionally different.…”

“…31 In the latter study, Taillardet et al demonstrated that the thymus-dependent, tetanus toxoid-polysaccharide conjugate formulation generated BM plasma cells with greater antibody secretion compared to a thymus-independent polysaccharide vaccine given with CpG adjuvant. 31 That study concluded that plasma cells activated by the different types of vaccines were functionally different. Finally, although not strictly comparable to our mouse study, it is nonetheless interesting that Kim et al have recently reported that a high-dose of influenza antigen induces a striking effect on the pattern of immune responses in elderly subjects.…”