B7-blocking agents, alone or in combination with cyclosporin A, induce antigen-specific anergy of human memory T cells.
T cell anergy refers to a functional state in which the cells are alive but unable to produce IL-2 after appropriate triggering. Lack of CD28 costimulation through CD80 and CD86 molecules on APC might play a causative role in anergy induction, as previously shown with T cell clones. We now developed a model of anergy induction in cultures of freshly isolated memory T cells. Addition of either CTLA-4Ig or blocking anti-CD80 and anti-CD86 mAbs, in combination with cyclosporin A, to cultures of PBMC with soluble Ag consistently resulted in Ag-specific unresponsiveness, as evidenced upon antigenic rechallenge. In most experiments, the presence of cyclosporin A was not required, and blocking the B7-CD28 interaction during antigenic stimulation was sufficient to induce unresponsiveness. Unresponsiveness was apparent at the level of T cell proliferation as well as at the level of IL-2 and IFN-gamma production, and T cell responses to unrelated Ags were intact. Induction of unresponsiveness correlated with lack of T cell proliferation in the induction culture and could largely be prevented by supplementing the induction cultures with rIL-2, indicating that lack of IL-2 was responsible for this altered functional state. Unresponsive T cells did not suppress the proliferation of autologous T cells in response to original or third-party Ags. On the other hand, culture with IL-2 and Ag could reverse established T cell unresponsiveness, pointing to anergy rather than deletion as the underlying mechanism. Anergy induction in freshly isolated memory T cells opens perspectives for treatment of autoimmune and allergic diseases.
Yi-qun
Z
Z
Department of Pathophysiology, Faculty of Medicine, Catholic University Leuven, Belgium.
Lorré
K
K
de Boer
M
M
Ceuppens
J L
JL
D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage*; D018122:B7-1 Antigen / Q000502:physiology*; D018106:CD28 Antigens / Q000502:physiology; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D017635:Clonal Anergy; D016572:Cyclosporine / Q000008:administration & dosage*; D006801:Humans; D018796:Immunoconjugates; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014373:Tuberculin / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007376:Interleukin-2; D014373:Tuberculin; D000069594:Abatacept; D016572:Cyclosporine