Distinct regulatory roles of lymphocyte costimulatory pathways on T helper type-2 mediated autoimmune disease

doi:10.1084/jem.183.4.1473

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Distinct regulatory roles of lymphocyte costimulatory pathways on T helper type-2 mediated autoimmune disease

L Biancone, G Andres, H Ahn, A Lim, C Dai, R Noelle, H Yagita, C De Martino and I Stamenkovic
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02129, USA.

We assessed the role of CD40-CD40L, cytotoxic T lymphocyte (CTL)A4/CD28- B7s, and CD2-CD48/CD58 lymphocyte costimulatory pathways in the development of mercury chloride (HgCl2)-induced autoimmune disease in mice, which is believed to be mediated by T helper (Th) subset Th2. Inhibition of CD40-CD40-L and CTLA4/CD28-B7s interactions by anti-CD40- L antibody and soluble CTLA4-immunoglobulin (Ig) fusion protein, respectively, abrogated the autoimmune disease without affecting interleukin 4 (IL-4) production, showing the importance of physical contact between T and B lymphocytes in the Th2-mediated process. In contrast, two anti-CD2 antibodies that have been shown to induce immunosuppression of Th1-mediated events exacerbated the autoantibody response and augmented IgG1, IgE, and IL-4 production, transforming a mild mesangial glomerulopathy into a severe systemic immune complex disease. These observations demonstrate that manipulation of lymphocyte accessory counterreceptor interactions may affect the course of Th2- associated autoimmune disease and suggest that signals resulting from CD2 engagement play an essential role in the regulation of the Th1-Th2 effector equilibrium.
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