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

Abstract

Protection against infections with Streptococcus pneumoniae is mediated by antibodies against the capsular polysaccharides (caps-PS). Here we show that in in vitro experiments CD4 + T lymphocytes stimulate and CD8 + T lymphocytes inhibit the human anti-caps-PS antibody response. Using antagonistic anti-CD40 and antagonistic anti-CD40 ligand (CD40L) monoclonal antibodies, we showed that the CD4 + T lymphocyte-mediated stimulation is dependent on the CD40-CD40L interaction. The role of CD40L was further illustrated by the observation that CD4 + T lymphocytes obtained from a patient with hyper-IgM syndrome were unable to enhance the immune response to caps-PS. Furthermore, CD4 + T lymphocytes from cord blood, which did not express CD40L in response to stimulation with caps-PS, failed to stimulate the antibody response of adult B lymphocytes to caps-PS. These in vitro findings were confirmed by in vivo experiments in which SCID/SCID mice were reconstituted with human mononuclear cells. Furthermore, we showed that caps-PS induce production of IL-4, IL-6, IL-10, and IFN-+ , and that this enhanced production was inhibited by blocking the CD40-CD40L interaction. This is the first demonstration that the human immune response to caps-PS, which is markedly regulated by T lymphocytes, is dependent on the CD40-CD40L interaction.

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

“…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). Also in humans, we were able to show in vitro and in vivo that CD4 ϩ T lymphocytes strongly enhance the anti-caps-PS immune response and that this activation was inhibited by administering blocking anti-CD40 or anti-CD40L Abs (10). We found that polysaccharides induced the expression of CD40L on T cells (10).…”

“…We found that polysaccharides induced the expression of CD40L on T cells (10). Moreover, CD4 ϩ T lymphocytes obtained from patients with X-linked hyperIgM syndrome were unable to stimulate the anti-caps-PS immune response, whereas CD4 ϩ T lymphocytes obtained from a healthy individual were able to do so (10). The aim of this study was 2-fold.…”

“…Also in humans, we were able to show in vitro and in vivo that CD4 ϩ T lymphocytes strongly enhance the anti-caps-PS immune response and that this activation was inhibited by administering blocking anti-CD40 or anti-CD40L Abs (10). We found that polysaccharides induced the expression of CD40L on T cells (10). Moreover, CD4 ϩ T lymphocytes obtained from patients with X-linked hyperIgM syndrome were unable to stimulate the anti-caps-PS immune response, whereas CD4 ϩ T lymphocytes obtained from a healthy individual were able to do so (10).…”

“…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).…”

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.…”