Cellular interactions involved in Th cell memory.

The cellular interactions involved in maintaining CD4+ T cell memory have hitherto not been identified. In this report, we have investigated the roles played by B cells and dendritic cells (DCs) in this process. We show that long-lasting Th cell memory depends on the presence of B cells, but that direct Ag presentation by B cells is not required. Instead, Ag presentation by DCs is critical for the survival of memory Th cells. DCs presenting specific Ag can be detected in animals long after immunization. These findings support a model in which B cells provide an environment in which Ags may be trapped and retained. This Ag is periodically presented to memory CD4+ T cells by DCs, providing an essential survival signal.

Role of B cells in maintaining helper T-cell memory.

The cellular interactions involved in maintaining CD4+ T-cell memory have hitherto not been identified. In this report, we have investigated the role played by B cells in this process. We show that that long-lasting helper T-cell memory depends on the presence of B cells, but that direct antigen presentation by B cells is not required. These findings provide new insights into the mechanisms which underlie helper T-cell memory. They also suggest that the efficacy of future vaccines will depend critically on the inclusion of B- as well as T-cell epitopes.

A novel method for enhancement of T independent responses.

Bacterial capsular polysaccharides are the major targets for vaccination against encapsulated bacteria but present problems when used for immunisation as they are T cell independent antigens (TI-II). TI-II antigens do not induce a memory response, but induce an antibody response which is of low magnitude and is predominantly IgM, with little or no isotype switching to IgG isotypes. This is because TI-II antigens do not induce T cell help. Such T cell help to B cells is mediated through up regulation of the CD40 ligand (CD154) on the activated T cell, which binds to CD40 inducing B cell activation, proliferation and isotype switching in conjunction with cytokines produced by the T cell. We have successfully mimicked this T cell help and induced very strong, isotype switched antibody responses to TI-II antigens by the simple addition of agonistic anti-CD40 antibodies to pneumococcal polysaccharides before immunisation.

Enhancement of T cell-independent immune responses in vivo by CD40 antibodies.

In this report we describe a potentially powerful method for vaccinating infants against encapsulated bacterial pathogens such as Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis. High levels of antibody directed against the polysaccharides of the bacterial capsule are normally protective. Unfortunately, the capsular polysaccharides are T cell-independent antigens (TI); lacking T-cell help, they induce only weak, predominantly IgM antibody responses, with infants responding especially poorly. T-cell help, given to B cells during responses to protein antigens, causes stronger antibody responses and isotype switching to the IgG isotypes. T-cell help is mainly mediated through ligation of the B-cell surface antigen, CD40, by its cognate T-cell ligand, CD154. Here we show that administering anti-CD40 monoclonal antibody to mice, along with pneumococcal polysaccharide, provides a substitute for T-cell help and results in the generation of strong, isotype-switched antibody responses, which are protective. The work points the way toward a possible effective and inexpensive means of protecting susceptible groups against important bacterial pathogens.

Memory B cell development but not germinal center formation is impaired by in vivo blockade of CD40-CD40 ligand interaction.

To study the role of the CD40-CD40 ligand interaction in the development of memory B cells and its level of action during primary antibody responses in vivo, mice were injected with a soluble CD40 fusion protein (sCD40-gamma 1), so as to block the interaction. The effects of the treatment on the primary antibody response were reminiscent of hyper-immunoglobulin M (IgM) syndrome (HIMG1): antigen-specific IgG responses were grossly inhibited whereas the IgM response was augmented severalfold. The latter observation suggests that there is a T-dependent, CD40 ligand-independent pathway of B cell activation that leads to IgM responses and that a significant component of the IgM in HIMG1 patients is derived from T-dependent responses. The secondary response was not readily blocked by sCD40-gamma 1 treatment, indicating a relative independence of CD40 ligation of antigen-experienced B cells. The most striking finding from these studies is that the development of memory B cell populations (measured by adoptive transfer) is grossly impaired by administration of sCD40-gamma 1 during the early induction phase of the response. It is surprising that although the generation memory is diminished, there is no quantitative difference in the development of germinal centers. Whereas entry of B cells into the memory cell pathway is dependent on CD40 ligation, the clonal expansion of the potential memory precursors in germinal centers seems not to require a CD40 signal.