Essential Role for CD40 Ligand Interactions in T Lymphocyte-Mediated Modulation of the Murine Immune Response to Pneumococcal Capsular Polysaccharides

Abstract

Protection against infection with pneumococci is provided by anti-capsular polysaccharide (caps-PS) Abs. We investigated whether CD40 ligand (CD40L) plays a role in T lymphocyte-mediated regulation of the immune response to caps-PS, which are considered thymus-independent Ags. Administration of MR1, an antagonist mAb against murine CD40L, in BALB/c mice immunized with Pneumovax resulted in an inhibition of the IgM and IgG Ab response for various caps-PS serotypes. Evidence for the involvement of CD4+ T lymphocytes in the Ab response to caps-PS was obtained in SCID/SCID mice that, when reconstituted with B lymphocytes and CD4+ T lymphocytes, mounted a higher specific IgM response compared with SCID/SCID mice reconstituted with only B lymphocytes. This helper effect of CD4+ T lymphocytes was abrogated by MR1. Blocking CD40L in vitro decreased the IgM response to caps-PS and abolished the helper effect of CD4+ T lymphocytes. CD8+ T lymphocyte-depleted murine spleen cells mounted a higher in vivo immune response than total murine spleen cells, which provided evidence for a suppressive role of CD8+ T lymphocytes on the anti-caps-PS immune response. CD4+ T lymphocyte-depleted murine spleen cells, leaving a B and CD8+ T lymphocyte fraction, elicited only a weak in vivo and in vitro Ab response, which was enhanced after MR1 administration. In summary, our data provide evidence that T lymphocytes contribute to the regulation of the anti-caps-PS immune response in a CD40L-dependent manner.

CD4+ T Lymphocytes Expressing CD40 Ligand Help the IgM Antibody Response to Soluble Pneumococcal Polysaccharides via an Intermediate Cell Type

“…Studies using the TI-2 Ags trinitrophenyl (TNP)-Ficoll or DNP-Ficoll (5-7) and one study using purified caps-PS serotype 6 (8) concluded that the Ab responses to these TI-2 Ags are independent of the CD40-CD40L interaction. By contrast, we more recently found that the Ab response to several caps-PS serotypes, including serotype 6, was dependent on the CD40-CD40L interaction (9,10). This was demonstrated in a murine model by showing that the helper effect of CD4 ϩ T lymphocytes and the inhibitory effect of CD8 ϩ T lymphocytes on the anti-caps-PS immune response in vivo and in vitro was abrogated by MR1, a blocking anti-CD40L Ab (9).…”

The human antibody response to pneumococcal capsular polysaccharides is dependent on the CD40‐CD40 ligand interaction

“…ELISA for detection of anti-caps-PS antibodies was performed as previously described [10]. For detection of human anti-caps-PS antibodies, peroxidase-conjugated goat-antihuman IgM and goat anti-human IgG in a dilution of 1/5,000 was added to the wells.…”

“…IgM antibodies and cytokine-producing cells ELISPOT assay for the detection of anti-caps-PS IgM antibodies was performed as previously described [10]. For detection of IgM-producing cells, alkaline phosphataseconjugated goat anti-human IgG was used.…”

“…Furthermore, it was observed that administration of an agonistic anti-CD40 monoclonal antibody (mAb) that mimics CD40L activity, to mice, along with pneumococcal caps-PS, generated a strong protective antibody response [9]. Finally, we recently demonstrated that the murine immune response to caps-PS was stimulated by CD4 + T lymphocytes and inhibited by CD8 + T lymphocytes and that these effects were mediated by the CD40-CD40L interaction [10]. Fig.…”

1α,25-Dihydroxyvitamin D3 modulates the murine antibody response to pneumococcal capsular polysaccharide serotype 3 through IL-12

“…However, T lymphocytes do modulate the anti-caps-PS antibody response: CD4 + T lymphocytes have a stimulatory effect, whereas CD8 + T lymphocytes have an inhibitory effect [5]. These regulatory effects are dependent on the CD40-CD40L interaction [6,7]. In addition to T lymphocytes, also antigen-presenting cells (APC) seem important in the antibody response to caps-PS.…”