BLOCKADE OF CD40-CD40 LIGAND PATHWAY INDUCES TOLERANCE IN MURINE CONTACT HYPERSENSITIVITY

Interactions between CD40 on antigen-presenting cells and its ligand ( CD40L) on T cells has been implicated in T cell-mediated immune respon ses. Previously, we have shown that contact hypersensitivity (CHS), a cell-mediated cutaneous immune response in reaction to haptens, could be subclassified based on whether the hapten primed for Th1 or Th2 cyt okines in cells isolated from draining lymph nodes. We also found that tolerance to a Th2-priming hapten could be induced only by simultane blockade of the CD40-CD40L and B7-CD28 at the time of sensitization. H ere we demonstrate that blockade of CD40-CD40L signaling alone induces long-lasting unresponsiveness to the Th1 hapten 2,4-dinitrofluorobenz ene (DNFB), and inhibits antigen-specific T cell proliferation in vitr o. We find that CD40-CD40L signaling is required in the sensitization but not elicitation phase of DNFB-induced CHS, as treatment of mice wi th anti-CD40L monoclonal antibody (mAb) does not affect the response t o hapten challenge in previously sensitized and untreated animals. Exa mination of cytokine production shows that anti-CD40L mAb decreases in terferon-gamma production by draining lymph node cells from DNFB-sensi tized mice, and reciprocally increases interleukin (IL)-4 production. Consistent with this Th1 to Th2 immune deviation, anti-CD40L mAb preve nts the induction of IL-12 mRNA in regional lymph nodes, an event whic h is normally seen within 12 h following hapten sensitization. In cont rast, suppression of CHS by CTLA4Ig decreased the production of all cy tokines by draining lymph node cells. Together, these data show that b lockade of the CD40-CD40L pathway by itself is sufficient to induce to lerance to DNFB-induced CHS, and that this is associated with blockade of IL-12 induction and Th1 to Th2 immune deviation.