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© The Rockefeller University Press, 0022-1007/1997/10/1119/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 7, October 6, 1997 1119-1128

Articles

Role of Interleukin 12 and Costimulators in T Cell Anergy In Vivo

Luk Van Parijs, Victor L. Perez, Andre Biuckians, Robert G. Maki, Cheryl A. London, and Abul K. Abbas

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.

Address correspondence to Dr. Abul K. Abbas, Brigham & Women's Hospital and Harvard Medical School, LMRC-521, 221 Longwood Ave., Boston, MA 02115. Phone: 617-732-6523; Fax: 617-732-5795. Present address for V.L. Perez is Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02108.

1 Abbreviations used in this paper: DO.11, DO.11.10 TCR.


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