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By
From the Immunology Research Division, Department of Pathology, Brigham & Women's Hospital
and Harvard Medical School, Boston, Massachusetts 02115
The induction of T cell anergy in vivo is thought to result from antigen recognition in the absence of co-stimulation and inflammation, and is associated with a block in T cell proliferation and Th1 differentiation. 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 from T cell receptor transgenic mice. The administration of IL-12 at the
time of tolerance induction stimulates Th1 differentiation, but does not promote antigen-specific T cell proliferation. Conversely, inhibiting 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 cells which have encountered immunogenic antigen. These results suggest that two processes contribute to the induction of anergy in vivo; CTLA-4 engagement, which leads to a block in the ability of T cells to proliferate to antigen,
and the absence of a prototypic inflammatory cytokine, IL-12, which prevents the differentiation of T cells into Th1 effector cells. The combination of IL-12 and anti-CTLA-4 antibody is
sufficient to convert a normally tolerogenic stimulus to an immunogenic one.
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