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 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.
Van Parijs
L
L
Immunology Research Division, Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Perez
V L
VL
Biuckians
A
A
Maki
R G
RG
London
C A
CA
Abbas
A K
AK
D000069594:Abatacept; D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000276:immunology; D060908:CTLA-4 Antigen; D002454:Cell Differentiation; D017635:Clonal Anergy; D005434:Flow Cytometry; D007108:Immune Tolerance; D018796:Immunoconjugates; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*
D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D011948:Receptors, Antigen, T-Cell; D018664:Interleukin-12; D000069594:Abatacept; D007371:Interferon-gamma; D010047:Ovalbumin