ROLE OF INTERLEUKIN-12 AND COSTIMULATORS IN T-CELL ANERGY IN-VIVO

The induction of T cell anergy in vivo is thought to result from antig en recognition in the absence of co-stimulation and inflammation, and is associated with a block in T cell proliferation and Th1 differentia tion. Here we have examined the role of interleukin (IL)-12, a potent inducer of Th1 responses, in regulating this process. T cell tolerance was induced by the administration of protein antigen without adjuvant in normal mice, and in recipients of adoptively transferred T cells f rom T cell receptor transgenic mice. The administration of IL-12 at th e time of tolerance induction stimulates Th1 differentiation, but does not promote antigen-specific T cell proliferation. Conversely, inhibi ting CTLA-4 engagement during anergy induction reverses the block in T cell proliferation, but does not promote full Th1 differentiation. T cells exposed to tolerogenic antigen in the presence of both IL-12 and anti-CTLA-4 antibody are not anergized, and behave identically to T c ells which have encountered immunogenic antigen. These results suggest that two processes contribute to the induction of anergy in vivo; CTL A-4 engagement, which leads to a block in the ability of T cells to pr oliferate to antigen, and the absence of a prototypic inflammatory cyt okine, IL-12, which prevents the differentiation of T cells into Th1 e ffector cells. The combination of IL-12 and anti-CTLA-4 antibody is su fficient to convert a normally tolerogenic stimulus to an immunogenic one.