Circumventing tolerance at the T cell or the antigen-presenting cell surface: antibodies that ligate CD40 and OX40 have different effects.

An adjuvant can be defined as an agent that non-specifically promotes the immune response to an accompanying antigen. Ligation of CD40 on the surface of the antigen-presenting cell leads to upregulation of OX40 ligand which, in turn, ligates OX40 on the activated T cell resulting in prolonged T cell proliferation/survival, boosting the immune response. Thus agonistic anti-CD40 and anti-OX40 might be viewed as "adjuvant antibodies" and have been shown in diverse experimental systems to either boost immune responses or prevent the establishment of immunological tolerance. Here we describe that both these antibodies are able to prevent the induction of tolerance induced using soluble peptide antigen. However, unlike lipopolysaccharide, they are not sufficient to convert tolerance to immunity (i.e. they are not true adjuvants in this system). Using mice that are prone to either Th1 or Th2 immunity under identical immunization conditions, we show that the effects of anti-OX40 are quantitative -- boosting whichever response is dominant. In contrast, anti-CD40 boosts Th1 immunity and converts a Th2 response to Th1. We conclude that, although these two antibodies seem to impact on the same molecular pathway of costimulation to prevent tolerance, their effects are qualitatively distinct and their use cannot be viewed as interchangeable.