An Inhibitor of CD28–CD80 Interactions Impairs CD28-Mediated Costimulation of Human CD4 T Cells

Author： Fine J.S. Macosko H.D. Justice L. Chou C-C. Jenh C-H. Narula S.K. Zavodny P.J.

ISSN： 0008-8749

Source： Cellular Immunology, Vol.191, Iss.1, 1999-01, pp. : 49-59

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Abstract

We have identified and characterized a microbial extract-derived inhibitor of T cell CD28-dependent costimulation, NP1835-2, utilizing an in vitro system in which anti-human CD3 antibody and a human CD80-Ig fusion protein are immobilized on protein A-coated microspheres. This system is CD28-CD80-dependent, as judged by the specific ability of anti-CD80 antibody or cytotoxic T lymphocyte antigen-4-Ig to block human CD4 T cell responses. Activation of CD4 T cells in this system in presence of NP1835-2 resulted in a concentration-dependent inhibition of T cell proliferation (IC₅₀ of 1–4 μg/ml), surface activation marker expression, and the production of many T cell cytokines, with the exception of TGFβ. Impairment of T cell activation correlated with a blockade of cell cycle progression at G₀/G₁ and was only partly restored by addition of 100 U/ml IL-2. No inhibition by NP1835-2 of T cell proliferation stimulated by plate-bound anti-CD3 antibody, phorbol 12-myristate 13-acetate + A23187, or P815 cells expressing the costimulatory molecule CD58 was observed. NP1835-2 was unable to modulate anti-IgM-stimulated B cell proliferation or LPS-induced monocyte activation. Suboptimal concentrations of NP1835-2 and cyclosporin together were able to impair T cell activation in an additive fashion. NP1835-2 was also able to inhibit the primary human MLR. These data indicate that NP1835-2 may belong to a class of molecules capable of selectively impairing CD28-mediated T cell costimulation and suggest its potential usefulness in the treatment of a variety of T cell-dependent diseases. Moreover, NP1835-2 may serve as a useful probe for investigating the mechanisms involved in T cell nonresponsiveness.