Role of interleukin 12 and costimulators in T cell anergy in vivo

• Published in: The Journal of experimental medicine Vol. 186; no. 7; pp. 1119 - 1128
• Main Authors: Van Parijs, L, Perez, V L, Biuckians, A, Maki, R G, London, C A, Abbas, A K
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 06.10.1997
• Subjects: Abatacept; Adoptive Transfer; Animals; Antibodies - immunology; Antigens, CD; Antigens, Differentiation - immunology; Antigens, Differentiation - metabolism; Autoimmune Diseases - immunology; Cell Differentiation; Clonal Anergy; CTLA-4 Antigen; Flow Cytometry; Immune Tolerance; Immunoconjugates; Inflammation - immunology; Interferon-gamma - metabolism; Interleukin-12 - immunology; Interleukin-12 - pharmacology; Mice; Mice, Inbred BALB C; Mice, Transgenic; Ovalbumin - administration & dosage; Ovalbumin - immunology; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; T-Lymphocytes - immunology; Th1 Cells - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.186.7.1119

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.