Circumventing tolerance at the T cell or the antigen‐presenting cell surface: Antibodies that ligate CD40 and OX40 have different effects

Abstract

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.

Effector and central memory T helper 2 cells respond differently to peptide immunotherapy

“…Naive OT-II cells are sensitive to PIT when pOVA is administered i.v. in PBS (21,22,24). We assessed therapeutic efficacy of PIT in AAI by administration of pOVA 2 d after Th2 cell transfer and 4 d before i.t.…”

“…This is different from the clinical setting where established T-celldriven pathology, by definition, presents with an increased frequency of antigen-experienced T cells (23). We, and others, have previously shown that application of tolerogenic peptide induces naive CD4 + T cells to enter a brief but abortive phase of proliferation that is followed by their wide-scale apoptotic deletion (21,22,24). This is most likely the result of insufficient costimulation from the antigen-presenting cell in the absence of innate immune triggers (21,22,24).…”

“…We, and others, have previously shown that application of tolerogenic peptide induces naive CD4 + T cells to enter a brief but abortive phase of proliferation that is followed by their wide-scale apoptotic deletion (21,22,24). This is most likely the result of insufficient costimulation from the antigen-presenting cell in the absence of innate immune triggers (21,22,24). However, several characteristics of antigen-experienced T cells hint that they may not necessarily respond to PIT in the same way.…”

The Net Effect of Costimulatory Blockers Is Dependent on the Subset and Activation Status of the Autoreactive T Cells

“…1), but had no effect on IL-2 production and enhanced IFN-␥ production (Fig. 2), suggesting that anti-CD40 signaling may generate additional cellular effects, such as triggering IL-12 production by APCs, thus allowing pathogenic T cell differentiation (32).…”

Peptide immunotherapy in experimental autoimmune encephalomyelitis

“…Co-administration of agonistic antibodies binding the co-stimulatory molecules CD40 or OX 40 at the time of PIT can prevent the induction of tolerance (substituting for the use of LPS). [32,33] This correlates with sustained T-cell numbers by driving the expression of anti-apoptotic molecules Bcl-2 and survivin in the responding T cells. These are dependent on OX 40 signaling, [34,35] which is mediated either directly by the anti-OX40 or indirectly by elevated OX40 ligand expression on the peptide-MHC-presenting APC, triggered by CD40 signaling driven by the anti-CD40.…”